JP5020073B2 - Factor Xa inhibitor - Google Patents

Description

This application claims the benefit of US Patent Application No. 60 / 580,899, filed Jun. 18, 2004, the contents of which are hereby incorporated by reference.

Statement of rights to inventions made under federal-funded research and development Not applicable.

Reference to the “Sequence Listing”, Table, or Computer Program List attachment submitted on a compact disc Not applicable.

BACKGROUND OF THE INVENTION Hemostasis, or bleeding control, is performed by surgical means or the physiological nature of vasoconstriction and coagulation. The invention particularly relates to blood clotting and methods by which it helps maintain the integrity of the mammal's circulation after injury, inflammation, disease, birth defects, dysfunction or other disruptions. Although platelets and blood coagulation are both involved in thrombus formation, certain components of the coagulation cascade are primarily responsible for the amplification or acceleration of processes involved in platelet aggregation and fibrin deposition.

  Thrombin is a major enzyme in the coagulation cascade and hemostasis. Thrombin plays a central role in thrombosis through its ability to catalyze the conversion of fibrinogen to fibrin and its potent platelet activating effect. As reviewed by Claeson, G., “Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System”, Blood Coag. Fibrinol., 5: 411-436 (1994) Direct or indirect inhibition of thrombin activity has been the focus of various recent anticoagulation strategies. Several classes of anticoagulants (ie, heparin, low molecular weight heparin, heparin-like compounds, and coumarins) that directly or indirectly affect thrombin are currently used in the clinic.

  Prototypes containing factor Xa (serine protease, an activated form of its factor X precursor and calcium ion binding, gamma carboxyglutamyl (Gla) -containing, vitamin K-dependent, member of the blood coagulation glycoprotein family) The lombinase complex converts zymogen, prothrombin, to active thrombin, thrombin. Unlike thrombin, which acts not only on specific receptors but on various protein substrates, factor Xa appears to have a single physiological substrate, namely prothrombin. It is thought that one molecule of factor Xa can generate up to 138 thrombin molecules (Elodi et al., Thromb. Res. 15: 617-619 (1979)). Direct inhibition of factor Xa as a way to inhibit it would be an effective anticoagulation strategy. Thus, it has been suggested that compounds that selectively inhibit factor Xa may be useful as in vitro diagnostic agents or for therapeutic administration in certain thrombotic disorders, eg, WO 94 / See Japanese Patent No. 13693 (Patent Document 1).

  A polypeptide from a blood-sucking organism has been reported which is a very potent and specific inhibitor of factor Xa. US Pat. No. 4,588,587 describes the anticoagulant activity in the saliva of Mexico Hill, Haementeria officinalis. Nutt, E. et al., “The Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveals a Repeated Internal Structure”, J. Biol. Chem., 263: 10162-10167 (1988) (Non-patent Document 3) Revealed that the main component of this saliva is antistasin (ATS), a polypeptide factor Xa inhibitor. As reported by Waxman, L., et al., “Tick Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa”, Science, 248: 593-596 (1990) (Non-Patent Document 4). Another potent and highly specific factor Xa inhibitor called anticoagulant peptide (TAP) has been isolated from a systemic extract of the mite, Ornithidoros moubata.

  Factor Xa inhibitor compounds that are not large polypeptide type inhibitors have also been reported (eg, Tidwell, RR et al., “Strategies for Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors”, Thromb. Res., 19 : 339-349 (1980) (Non-Patent Document 5); Turner, AD et al., “P-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin”, Biochemistry, 25: 4929-4935 (1986) Patent Document 6); Hitomi, Y. et al., “Inhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System”, Haemostasis, 15: 164-168 (1985) (Non-Patent Document 7); Sturzebecher , J. et al., “Synthetic Inhibitors of Bovine Factor Xa and Thrombin. Comparison of Their Anticoagulant Efficiency”, Thromb. Res., 54: 245-252 (1989) (Non-Patent Document 8); Kam, CM et al. , “Mechanism Based Isocoumarin Inhibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagulants”, Biochemistry, 27: 2547-2557 (1988) 9); Hauptmann, J. et al., “Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors”, Thromb. Haemost., 63: 220-223 (1990) (Non-patent Document 10)) .

Others are small molecule organic compounds, such as nitrogen-containing heterocyclic compounds having an amidino substituent, wherein two functional groups of the compound can bind to factor Xa at two of its active sites. Factor Xa inhibitors have been reported. For example, International Publication No. 98/28269 (Patent Document 3) describes pyrazole compounds having a terminal C (= NH) -NH ₂ group; International Publication No. 97/21437 (Patent Document 4) Benzimidazole compounds substituted with a basic group linked to a naphthyl group via a linear or branched alkylene, C (═O) or S (═O) ₂ bridging group are described; / 10316 (Patent Document 5) has 4-phenyl-N-alkylamidino-piperidine and 4-phenoxy-N-alkylamidino-piperidine groups linked to a 3-amidinophenyl group via a carboxamide alkyleneamino bridge Compounds are described; and EP 798295 describes compounds having a 4-phenoxy-N-alkylamidino-piperidine group linked to an amidinonaphthyl group via a substituted or unsubstituted sulfonamide or carboxamide bridging group .

  There is a need for effective therapeutic agents for the regulation of hemostasis and for the prevention and treatment of other pathological processes in the vasculature induced by thrombin such as thrombus formation, restenosis and inflammation . In particular, there continues to be a need for compounds that selectively inhibit factor Xa or its precursors. There is a need for compounds having different combinations of cross-linking groups and functional groups than those previously found, particularly those that selectively or preferentially bind to factor Xa. Compounds that bind to Factor Xa more than thrombin are desirable, particularly compounds that have good bioavailability and / or solubility.

International Publication No.94 / 13693 U.S. Pat.No. 4,588,587 International Publication No.98 / 28269 International Publication No. 97/21437 International Publication No.99 / 10316 Claeson, G., “Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System”, Blood Coag. Fibrinol., 5: 411-436 (1994) Elodi et al., Thromb. Res. 15: 617-619 (1979) Nutt, E. et al., “The Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveals a Repeated Internal Structure”, J. Biol. Chem., 263: 10162-10167 (1988) Waxman, L., et al., “Tick Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa”, Science, 248: 593-596 (1990) Tidwell, R.R. et al., “Strategies for Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors”, Thromb. Res., 19: 339-349 (1980) Turner, A.D. et al., “P-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin”, Biochemistry, 25: 4929-4935 (1986) Hitomi, Y. et al., “Inhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System”, Haemostasis, 15: 164-168 (1985) Sturzebecher, J. et al., “Synthetic Inhibitors of Bovine Factor Xa and Thrombin. Comparison of Their Anticoagulant Efficiency”, Thromb. Res., 54: 245-252 (1989) Kam, C.M. et al., “Mechanism Based Isocoumarin Inhibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagulants”, Biochemistry, 27: 2547-2557 (1988) Hauptmann, J. et al., “Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors”, Thromb. Haemost., 63: 220-223 (1990)

およびその薬学的に許容される塩を提供する。式(I)において、Aは、ハロゲン、オキソ、R^A、-OR^A、N(R^A)₂、CO₂R^A、CON(R^A)₂、S(O)₂R^A、S(O)₂N(R^A)₂、X¹OR^A、X¹CO₂R^A、X¹CON(R^A)₂、X¹N(R^A)₂から選択される0〜4個の置換基を有する、ベンゼン、1〜3個の窒素原子を含む6員複素環または1〜4個の窒素、酸素、もしくは硫黄原子を含む5員複素環を表し、ここでR^Aはそれぞれ、H、C_1-8アルキル、C_2-8アルケニル、C_2-8アルキニルから独立に選択されるか、または任意で同じ原子に結合している二つのR^Aは化合して3-、4-、5-、6-もしくは7-員環を形成し；RはHおよびC_1-4アルキルからなる群より選択されるメンバーを表し；R¹はハロゲン、C_1-8アルキル、C_2-8アルケニルおよびC_2-8アルキニルからなる群より選択されるメンバーを表し；R²はH、C_1-8アルキル、-X-OR^2a、-X-SR^2a、-X-COR^2a、-X-CO₂R^2aおよび-X-N(R^2a)₂からなる群より選択されるメンバーを表し、ここでXはC_1-8アルキレンであり、かつR^2aはそれぞれ、HおよびC_1-8アルキルから独立に選択されるか、または任意で同じ窒素原子に結合している二つのR^2a基は化合して4-、5-、6-もしくは7-員環を形成する。 SUMMARY OF THE INVENTION In one aspect, the present invention provides a compound having the formula:

And pharmaceutically acceptable salts thereof. In the formula (I), A is halogen, oxo, R ^A , —OR ^A , N (R ^A ) ₂ , CO ₂ R ^A , CON (R ^A ) ₂ , S (O) ₂ R ^A , S (O ) 0 to 4 substituents selected from ₂ N (R ^A ) ₂ , X ¹ OR ^A , X ¹ CO ₂ R ^A , X ¹ CON (R ^A ) ₂ , X ¹ N (R ^A ) ₂ Benzene, a 6-membered heterocyclic ring containing 1 to 3 nitrogen atoms or a 5-membered heterocyclic ring containing 1 to 4 nitrogen, oxygen or sulfur atoms, wherein R ^A is H, C ₁ , respectively. Two R ^A independently selected from _-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, or optionally bonded to the same atom are combined to form 3-, 4-, 5-, Forming a 6- or 7-membered ring; R represents a member selected from the group consisting of H and C _1-4 alkyl; R ¹ is halogen, C _1-8 alkyl, C _2-8 alkenyl and C _{2 Represents} a member selected from the group consisting of _-8 alkynyl; R ² is H, C _1-8 alkyl, -X-OR ^2a , -X-SR ^2a , -X-COR ^2a , -X-CO ₂ R ^2a And represents a member selected from the group consisting of -XN (R ^2a ) ₂ , wherein X is C _1-8 alkylene, and R ^2a is independently selected from H and C _1-8 alkyl, respectively. Or optionally two R ^2a groups bonded to the same nitrogen atom combine to form a 4-, 5-, 6- or 7-membered ring.

The letter W represents a moiety having a formula selected from (a), (b), and (c):

With respect to formula (b), the symbols Z ¹ , Z ² , and Z ³ each independently represent N, C, or CH, provided that ^{two of} Z ¹ , Z ² , and Z ³ are other than N.

For formulas (a) and (b), the subscript n is an integer from 0 to 3 and the subscript m is an integer from 0 to 1. The symbol R ⁴ represents, at each occurrence, halogen, -OR ^4a , -OC (O) R ^4a , -NR ^4a R ^4b , -SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R ^4b , -R ^4c , -CN, -NO ₂ , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , -OC (O) NR ^4a R ^4b , -NR ^4b C (O) R ^4a , -NR ^4b C (O) ₂ R ^4c , -NR ^4a -C (O) NR ^4a R ^4b , -X ¹ OR ^4a , -X ¹ OC (O) R ^4a , -X ¹ NR ^4a R ^4b , -X ¹ SR ^4a , -X ¹ S (O) R ^4a , -X ¹ S (O) ₂ R ^4a , -X ¹ CN, -X ¹ NO ₂ , -X ¹ CO ₂ R ^4a , -OX ¹ CO ₂ R ^4a , -X ¹ CONR ^4a R ^4b , -OX ¹ CONR ^4a R ^4b , -X ¹ C (O) R ^4a , -OX ¹ NR ^4a R ^4b , -S (O ) X ¹ NR ^4a R ^4b , -S (O) ₂ X ¹ NR ^4a R ^4b , -X ¹ OC (O) NR ^4a R ^4b , -X ¹ NR ^4a C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a C (O) NR ^4a R ^4b , -Y, -X ¹ -Y, -OY, -NR ^4a Y, -SY, -S (O) Y and- Represents a member selected from the group consisting of S (O) ₂ Y. Similarly, R ^{4 ′} is -C (= NH) R ^4a , -C (= NR ^4c ) R ^4a , -C (= NH) NR ^4a R ^4b , -C (= NR ^4c ) NR ^4a R ^4b ,- C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b , -X ² -C (= NH) NR ^4a R ^4b , -X ² -C (= NR ^4c ) NR ^4a R ^4b , -X ² -C ( = N ⁺ R ^4c R ^4c ) NR ^4a R ^4b and -C (= NR ^4a ) NR ^4a represents a member selected from the group consisting of -Y, where Y is halogen, oxo, -OR ^4a , -OC ( O) R ^4a , -NR ^4a R ^4b , -R ^4c , -SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R ^4b , -CN, -NO ₂ , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , -NR ^4b C (O) R ^4a , -NR ^4b C (O) ₂ R ^4c , -X ¹ R ^4a , -X ¹ OR ^4a , -X ¹ SR ^4a , -X ¹ S (O) R ^4a , -X ¹ S (O) ₂ R ^4a , -X ¹ CN, -X ¹ NO ₂ , -X ¹ CO ₂ R ^4a , -X ¹ CONR ^4a R ^4b , -X ¹ C (O) R ^4a , -OX ¹ NR ^4a R ^4b , -S (O) X ¹ NR ^4a R ^4b , -S (O) ₂ X ¹ NR ^4a R ^4b , -X ¹ OC (O) NR ^4a R ^4b , -X ¹ NR ^4b C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a -C (O) NR ^4a R ^4b , -X ¹ OC (O) R ^4a , -X ¹ NR ^4a R ^4b , -OX ¹ OR ^4a , -OX ¹ NR ^4a R ^4b , -OX ¹ CO ₂ R ^4a , -OX ¹ CONR ^4a R ^4b , -N ^{1 to 4} selected from the group consisting of R ^4b -X ¹ OR ^4a , -NR ^4b -X ¹ NR ^4a R ^4b , -NR ^4b -X ¹ CO ₂ R ^4a , and -NR ^4b -X ¹ CONR ^4a R ^4b 5 or 6 membered aryl, heterocyclyl or aryl-C _1-2 alkyl, optionally substituted with 3 substituents; X ¹ and X ² are C _1-4 alkylene, C _2-4 alkenylene, respectively And R ^4a and R ^4b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C ₃ , and C _3-4 alkynylene. Independently selected from the group consisting of _-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl; R each ^4c, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl , C _2-8 alkynyl, aryl, heteroaryl, selected aryl -C _1-4 alkyl, and more independently aryloxy -C _1-4 group consisting of alkyl, and optionally R ^4a, of R ^4b and R ^4c Any two, when part of a common R ⁴ or R ^{4 ′} substituent, combine with the atoms to which each is attached to have 0 to 2 additional heteroatoms as ring members, Saturated or unsaturated, 4-9 membered monocyclic or bicyclic rings can be formed. In addition, R ^4a , R ^4b and R ^4c are each —OH, oxo, —R ^m , —OR ^m , —OC (O) NHR ^m , —OC (O) N (R ^m ) ₂ , —SH, -SR ^m -S (O) R ^m , -S (O) ₂ R ^m , -SO ₂ NH ₂ , -S (O) ₂ NHR ^m , -S (O) ₂ N (R ^m ) ₂ , -NHS (O) ₂ R ^m , -NR ^m S (O) ₂ R ^m , -C (O) NH ₂ , -C (O) NHR ^m , -C (O) N (R ^m ) ₂ , -C (O ) R ^m , -NHC (O) R ^m , -NR ^m C (O) R ^m , -NHC (O) NH ₂ , -NR ^m C (O) NH ₂ , -NR ^m C (O) NHR ^m , -NHC (O) NHR ^m , -NR ^m C (O) N (R ^m ) ₂ , -NHC (O) N (R ^m ) ₂ , -CO ₂ H, -CO ₂ R ^m , -NHCO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -NH ₂ , -NHR ^m , -N (R ^m ) ₂ , -NR ^m S (O) NH ₂ and -NR ^m S (O) ₂ It may be further substituted with 1 to 3 members selected from the group consisting of NHR ^m , wherein each R ^m is independently unsubstituted C _1-6 alkyl, benzyl, or each bonded. To form a saturated 4, 5, 6 or 7 membered ring with 0 to 2 additional heteroatoms as ring members.

Then with respect to formula (c), the symbols R ⁵ is _{^{-R 5a, -CO 2 R 5c,}} -CONR 5a R 5b, -C (O) R 5a, -C (= NR 5a) NR 5a R 5b, -C (= N ⁺ R ^5c R ^5c ) NR ^5a R ^5b , -C (= NR ^5a ) R ^5a , -C (= NR ^5a ) Y ¹ , -X ³ OR ^5a , -X ³ OC (O) R ^5a , -X ³ NR ^5a R ^5b , -X ³ SR ^5a , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^5a , -X ³ CONR ^5a R ^5b , -X ³ C (O) R ^5a , -X ³ OC (O) NR ^5a R ^5b , -X ³ NR ^5a C (O) R ^5a , -X ³ NR ^5b C (O) ₂ R ^5c , -X ³ NR ^5a C (O) NR ^5a R ^5b represents a member selected from the group consisting of -X ³ -C (= NR ^5a ) NR ^5a R ^5b , -Y ¹ , and -X ³ -Y ¹ , where Y ¹ is halogen, -OR ^5a , -OC (O) R ^5a, -NR ^5a R ^5b , -R ^5c , -SR ^5a , -CN, -NO ₂ , -CO ₂ R ^5a , -CONR ^5a R ^5b , -C (O) R ^5a ,- NR ^5b C (O) R ^5a , -NR ^5b C (O) ₂ R ^5C , -X ³ OR ^5a , -X ³ SR ^5a , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^5a , -X ³ CONR ^5a R ^5b , -X ³ C (O) R ^5a , -X ³ OC (O) NR ^5a R ^5b , -X ³ NR ^5b C (O) R ^5a , -X ³ NR ^5b C ( O) ₂ R ^5c , -X ³ NR ^5a -C (O) NR ^5a R ^5b , -X ³ OC (O) R ^5a , -X ³ NR ^5a R ^5b , -OX ³ OR ^5a ,- OX ³ NR ^5a R ^5b , -OX ³ CO ₂ R ^5a , -OX ³ CONR ^5a R ^5b , -NR ^5b -X ³ OR ^5a , -NR ^5b -X ³ NR ^5a R ^5b , -NR ^5b -X ³ CO 5 or 6-membered aryl or heteroaryl ring or aryl-C optionally substituted with 1 to 3 substituents selected from the group consisting of ₂ R ^5a , and —NR ^5b —X ³ CONR ^5a R ^5b _1-2 alkyl, wherein X ³ is a member independently selected from the group consisting of C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene; R ^5a and R ^5b are each Hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-, respectively Independently selected from the group consisting of C _1-4 alkyl, and aryloxy-C _1-4 alkyl; R ^5c is C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, respectively. Independently from the group consisting of alkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl And optionally any two of R ^5a , R ^5b, and R ^5c , when part of a common R ⁵ substituent, combine with the atom to which each is bonded to 0-1 Saturated 4, 5, 6 or 7 membered rings can be formed having as a ring member any of the following heteroatoms. In addition, R ^5a , R ^5b and R ^5c are -OH, -OR ⁿ , -OC (O) NHR ⁿ , -OC (O) N (R ⁿ ) ₂ , -SH, -SR ⁿ -S ( O) R ⁿ , -S (O) ₂ R ⁿ , -SO ₂ NH ₂ , -S (O) ₂ NHR ⁿ , -S (O) ₂ N (R ⁿ ) ₂ , -NHS (O) ₂ R ⁿ , -NR ⁿ S (O) ₂ R ⁿ , -C (O) NH ₂ , -C (O) NHR ⁿ , -C (O) N (R ⁿ ) ₂ , -C (O) R ⁿ , -NHC (O) R ⁿ , -NR ⁿ C (O) R ⁿ , -NHC (O) NH ₂ , -NR ⁿ C (O) NH ₂ , -NR ⁿ C (O) NHR ⁿ , -NHC (O) NHR ⁿ , -NR ⁿ C (O) N (R ⁿ ) ₂ , -NHC (O) N (R ⁿ ) ₂ , -CO ₂ H, -CO ₂ R ⁿ , -NHCO ₂ R ⁿ , -NR ⁿ CO ₂ From the group consisting of R ⁿ , -CN, -NO ₂ , -NH ₂ , -NHR ⁿ , -N (R ⁿ ) ₂ , -NR ⁿ S (O) NH ₂ and -NR ⁿ S (O) ₂ NHR ⁿ It may be further substituted with 1 to 3 members selected, wherein each R ⁿ is independently unsubstituted C _1-6 alkyl or benzyl.

  The present invention is a method of preventing or treating a mammalian condition characterized by chemical intermediates, pharmaceutical compositions and undesirable thrombosis, wherein the mammal is administered a therapeutically effective amount of a compound of the present invention. Further provided is a method comprising steps. Such conditions include acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, obstructive coronary thrombosis after thrombolytic treatment or coronary angioplasty, thrombotic cerebrovascular syndrome, embolism Seizures, thrombotic seizures, transient ischemic seizures, venous thrombosis, deep vein thrombosis, pulmonary embolism, coagulopathy, disseminated intravascular coagulation, thrombocytopenic thrombotic purpura, obstructive thrombotic vasculitis, Thrombotic diseases associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, heart or other intravascular catheterization, intraaortic balloon pumps, coronary stents or thrombus associated with the use of devices such as heart valves This includes, but is not limited to, sexual complications and conditions that require prosthetic tube fitting.

  The present invention further provides a method of inhibiting clotting of a blood sample, the method comprising contacting the sample with a compound of the present invention.

Detailed Description of the Invention Abbreviations and Definitions The term `` alkyl '' as such or as part of another substituent, unless otherwise stated, means the indicated number of carbon atoms (i.e., C _1-8 is Means a straight or branched hydrocarbon group having 1-8 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. . The term “alkenyl” refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term “alkynyl” refers to an unsaturated alkyl group having one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1 -And 3-propynyl, 3-butynyl, and higher homologs and isomers are included. The term “cycloalkyl” has the indicated number of ring atoms (eg, C _3-6 cycloalkyl) and is fully saturated or no more than one double bond between the vertices of the ring. Means a hydrocarbon ring. When “cycloalkyl” is used in combination with “alkyl”, such as C _3-5 cycloalkyl-alkyl, the cycloalkyl moiety will have 3 to 5 carbon atoms, while the alkyl moiety is 1 An alkylene moiety having ˜3 carbon atoms (eg —CH ₂ —, —CH ₂ CH ₂ — or —CH ₂ CH ₂ CH ₂ —).

The term “alkylene” refers to a divalent group derived from an alkane, as exemplified by —CH ₂ CH ₂ CH ₂ CH ₂ — by itself or as part of another substituent. Typically, an alkyl (or alkylene) group will have 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A “lower alkyl” or “lower alkylene” is a short chain alkyl or alkylene, generally having 4 or fewer carbon atoms.

“Alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy) are used in their ordinary sense and are each alkyl bonded to the rest of the molecule through an oxygen, amino, or sulfur atom. Means group. In addition, for dialkylamino groups (typically provided in —NR ^a R ^b or variations thereof), the alkyl moieties may be the same or different and combine with the nitrogen atom to which each is attached. A ~ 7 membered ring can also be formed. Therefore, the group represented by —NR ^a R ^b includes piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.

The term “halo” or “halogen”, by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom unless otherwise specified. In addition, terms such as “haloalkyl” will include monohaloalkyl and polyhaloalkyl. For example, the term “C _1-4 haloalkyl” will include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

  The term “aryl”, unless stated otherwise, is polysaturated, typically aromatic, which may be a single ring or multiple rings (up to 3 rings) that are fused or covalently bonded. Means a hydrocarbon group. The term “heteroaryl” refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized. And the nitrogen atom is optionally quaternized. A heteroaryl group may be attached to the remainder of the molecule through a heteroatom or a carbon atom. Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl are included. Unless stated otherwise, the substituents for each of the aforementioned aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

  For brevity, the term “aryl” when used in combination with other terms (eg, aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term “arylalkyl” includes groups wherein an aryl group is bonded to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, etc.).

  The term “heterocycle” or “heterocycle” means a saturated or unsaturated non-aromatic cyclic group containing at least one sulfur, nitrogen or oxygen heteroatom. Each heterocycle can be attached at any available ring carbon or heteroatom. Each heterocycle may have one or more rings. If there are multiple rings, they may be fused or covalently bonded. Each heterocycle must contain at least one heteroatom (typically 1-5 heteroatoms) selected from nitrogen, oxygen or sulfur. Preferably, these groups contain 0-5 nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably, these groups contain 0 to 3 nitrogen atoms, 0 to 1 sulfur atoms and 0 to 1 oxygen atoms. Non-limiting examples of heterocyclic groups include benzene, pyridine, pyridimidine, pyrazine, morpholin-3-one, piperazin-2-one, pyridin-2-one, piperidine, morpholine, piperazine, isoxazole, isothiazole, Pyrazole, imidazole, oxazole, thiazole, isoxazoline, pyrazoline, imidazoline, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1 , 2,4-oxadiazole, 1,2,4-thiadiazole, pyrazol-5-one, pyrrolidine-2,5-dione, imidazolidine-2,4-dione, pyrrolidine, pyrrole, furan, thiophene, etc. It is.

  The aforementioned terms in some embodiments (eg, “aryl” and “heteroaryl”) will include both substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are shown below. For simplicity, the terms aryl and heteroaryl will mean substituted or unsubstituted forms as shown below.

Substituents for aryl and heteroaryl groups vary and are generally from -halogen, -oxo, -OR ', -OC (O) R', from a number ranging from zero to the total available valence of the aromatic ring system. -NR'R ", - SR ', - R', - CN, -NO 2, -CO 2 R ', - CONR'R", - C (O) R', - OC (O) NR'R " , -NR "C (O) R ', - NR" C (O) 2 R' ,, - NR'-C (O) NR "R ''', - NH-C (NH 2) = NH, - NR'C (NH ₂ ) = NH, -NH-C (NH ₂ ) = NR ', -S (O) R', -S (O) ₂ R ', -S (O) ₂ NR'R ", Selected from —NR ′S (O) ₂ R ″, —N ₃ , perfluoro (C ₁ -C ₄ ) alkoxy, and perfluoro (C ₁ -C ₄ ) alkyl; where R ′, R ″ and R ″ 'Is hydrogen, C _1-8 alkyl, C _3-6 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) -C _1-4 alkyl, and are independently selected from substituted aryloxy -C _1-4 alkyl. other suitable substituents, alkylene ream of 1 to 4 carbon atoms It includes aryl substituents mentioned above which are bonded to the ring atom in the chain.

Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC (O)-(CH ₂ ) _q -U-, where T and U are independent Are —NH—, —O—, —CH ₂ — or a single bond, and q is an integer of 0-2. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced with a substituent of the formula -A- (CH ₂ ) _r -B-, where A and B are independently -CH _2- , -O-, -NH-, -S-, -S (O)-, -S (O) _2- , -S (O) ₂ NR'- or a single bond, r is 1 It is an integer of ~ 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced with substituents of the formula — (CH ₂ ) _s —X— (CH ₂ ) _t —, where s and t are independently integers of 0 to 3, X is -O -, - NR '-, - S -, - S (O) -, - S (O) 2 -, or -S (O) ₂ NR '-. The substituent R ′ in —NR′— and —S (O) ₂ NR′— is selected from hydrogen or unsubstituted C _1-6 alkyl.

  As used herein, the term “heteroatom” will include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

  The term “pharmaceutically acceptable salts” refers to salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. Will be included. Where a compound of the invention contains a relatively acidic functional group, base addition by contacting the neutral form of such compound with a sufficient amount of the desired base, neat or in a suitable inert solvent. A salt can be obtained. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganous, manganous, potassium, sodium, zinc, etc. Is included. Salts derived from pharmaceutically acceptable organic bases include arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperazine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, Primary, secondary and tertiary amines including substituted amines such as tripropylamine, tromethamine, cyclic amines, natural amines and the like are included. Where a compound of the present invention contains a relatively basic functional group, the neutral form of such compound is contacted with a sufficient amount of the desired acid in neat or a suitable inert solvent to produce an acid. Addition salts can be obtained. Examples of pharmaceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, iodide. Derived from inorganic acids such as hydrogen acid or phosphorous acid, as well as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p -Salts derived from relatively non-toxic organic acids such as tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like. Also included are salts of amino acids such as arginine salts and salts of organic acids such as glucuronic acid or galacturonic acid (eg, Berge, SM, et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977 , 66, 1-19). Certain compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into base or acid addition salts.

  The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties such as solubility in polar solvents, but otherwise the salt is equivalent to the parent compound for the purposes of the present invention.

  In addition to salt forms, the present invention also provides prodrug-type compounds. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

  Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, for the uses contemplated by the present invention, all physical types are equivalent and are intended to be within the scope of the present invention.

Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (eg, separate enantiomers) are all intended to be encompassed within the scope of the present invention. The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compound may be radiolabeled with a radioisotope such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). All isotopic variants of the compounds of the invention are intended to be included within the scope of the invention, whether radioactive or not.

およびその薬学的に許容される塩を提供する。式(I)において、Aは、ハロゲン、オキソ、R^A、-OR^A、N(R^A)₂、CO₂R^A、CON(R^A)₂、S(O)₂R^A、S(O)₂N(R^A)₂、X¹OR^A、X¹CO₂R^A、X¹CON(R^A)₂、X¹N(R^A)₂から選択される0〜4個の置換基を有する、ベンゼン、1〜3個の窒素原子を含む6員複素環または1〜4個の窒素、酸素、もしくは硫黄原子を含む5員複素環を表し、ここでR^Aはそれぞれ、H、C_1-8アルキル、C_2-8アルケニル、C_2-8アルキニルから独立に選択されるか、または任意で同じ原子に結合している二つのR^Aは化合して3-、4-、5-、6-もしくは7-員環を形成し；RはHおよびC_1-4アルキルからなる群より選択されるメンバーを表し；R¹はハロゲン、C_1-8アルキル、C_2-8アルケニルおよびC_2-8アルキニルからなる群より選択されるメンバーを表し；R²はH、C_1-8アルキル、-X-OR^2a、-X-SR^2a、-X-COR^2a、-X-CO₂R^2aおよび-X-N(R^2a)₂からなる群より選択されるメンバーを表し；ここでXはC_1-8アルキレンであり、かつR^2aはそれぞれ、HおよびC_1-8アルキルからなる群より独立に選択されるか、または任意で同じ窒素原子に結合している二つのR^2a基は化合して4-、5-、6-もしくは7-員環を形成する。R²が存在し、かつH以外である態様について、好ましい態様群はR²が結合している炭素が(R)-立体化学配置を有するものである。 Overview Embodiment Compounds of the Invention In one aspect, the invention provides a compound having the formula:

And pharmaceutically acceptable salts thereof. In the formula (I), A is halogen, oxo, R ^A , —OR ^A , N (R ^A ) ₂ , CO ₂ R ^A , CON (R ^A ) ₂ , S (O) ₂ R ^A , S (O ) 0 to 4 substituents selected from ₂ N (R ^A ) ₂ , X ¹ OR ^A , X ¹ CO ₂ R ^A , X ¹ CON (R ^A ) ₂ , X ¹ N (R ^A ) ₂ Benzene, a 6-membered heterocyclic ring containing 1 to 3 nitrogen atoms or a 5-membered heterocyclic ring containing 1 to 4 nitrogen, oxygen or sulfur atoms, wherein R ^A is H, C ₁ , respectively. Two R ^A independently selected from _-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, or optionally bonded to the same atom are combined to form 3-, 4-, 5-, Forming a 6- or 7-membered ring; R represents a member selected from the group consisting of H and C _1-4 alkyl; R ¹ is halogen, C _1-8 alkyl, C _2-8 alkenyl and C _{2 Represents} a member selected from the group consisting of _-8 alkynyl; R ² is H, C _1-8 alkyl, -X-OR ^2a , -X-SR ^2a , -X-COR ^2a , -X-CO ₂ R ^2a And represents a member selected from the group consisting of -XN (R ^2a ) ₂ ; wherein X is C _1-8 alkylene and R ^2a is independently from the group consisting of H and C _1-8 alkyl, respectively Two R ^2a groups, selected or optionally attached to the same nitrogen atom, combine to form a 4-, 5-, 6- or 7-membered ring. For embodiments in which R ² is present and is other than H, preferred groups of embodiments are those in which the carbon to which R ² is attached has the (R) -stereochemical configuration.

式中、波線は分子の残部への結合点を示す。 The letter W represents a moiety having a formula selected from (a), (b), and (c):

In the formula, the wavy line indicates the point of attachment to the rest of the molecule.

With respect to formula (b), the symbols Z ¹ , Z ² , and Z ³ each independently represent N, C, or CH, provided that ^{two of} Z ¹ , Z ² , and Z ³ are other than N. The pyridyl nitrogen may be para (Z ¹ (4-pyridyl)), meta (Z ² (3-pyridyl)) or ortho (Z ³ (2-pyridyl)) relative to the A ring bond.

For formulas (a) and (b), the subscript n is an integer from 0 to 3 and the subscript m is an integer from 0 to 1. The symbol R ⁴ represents, at each occurrence, halogen, -OR ^4a , -OC (O) R ^4a , -NR ^4a R ^4b , -SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R ^4b , -R ^4c , -CN, -NO ₂ , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , -OC (O) NR ^4a R ^4b , -NR ^4b C (O) R ^4a , -NR ^4b C (O) ₂ R ^4c , -NR ^4a -C (O) NR ^4a R ^4b , -X ¹ OR ^4a , -X ¹ OC (O) R ^4a , -X ¹ NR ^4a R ^4b , -X ¹ SR ^4a , -X ¹ S (O) R ^4a , -X ¹ S (O) ₂ R ^4a , -X ¹ CN, -X ¹ NO ₂ , -X ¹ CO ₂ R ^4a , -OX ¹ CO ₂ R ^4a , -X ¹ CONR ^4a R ^4b , -OX ¹ CONR ^4a R ^4b , -X ¹ C (O) R ^4a , -OX ¹ NR ^4a R ^4b , -S (O ) X ¹ NR ^4a R ^4b , -S (O) ₂ X ¹ NR ^4a R ^4b , -X ¹ OC (O) NR ^4a R ^4b , -X ¹ NR ^4a C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a C (O) NR ^4a R ^4b , -Y, -X ¹ -Y, -OY, -NR ^4a Y, -SY, -S (O) Y and- Represents a member selected from the group consisting of S (O) ₂ Y. Similarly, R ^{4 ′} is -C (= NH) R ^4a , -C (= NR ^4c ) R ^4a , -C (= NH) NR ^4a R ^4b , -C (= NR ^4c ) NR ^4a R ^4b ,- C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b , -X ² -C (= NH) NR ^4a R ^4b , -X ² -C (= NR ^4c ) NR ^4a R ^4b , -X ² -C ( = N ⁺ R ^4c R ^4c ) NR ^4a R ^4b and -C (= NR ^4a ) NR ^4a represents a member selected from the group consisting of -Y, where Y is halogen, oxo, -OR ^4a , -OC ( O) R ^4a , -NR ^4a R ^4b , -R ^4c , -SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R ^4b , -CN, -NO ₂ , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , -NR ^4b C (O) R ^4a , -NR ^4b C (O) ₂ R ^4c , -X ¹ R ^4a , -X ¹ OR ^4a , -X ¹ SR ^4a , -X ¹ S (O) R ^4a , -X ¹ S (O) ₂ R ^4a , -X ¹ CN, -X ¹ NO ₂ , -X ¹ CO ₂ R ^4a , -X ¹ CONR ^4a R ^4b , -X ¹ C (O) R ^4a , -OX ¹ NR ^4a R ^4b , -S (O) X ¹ NR ^4a R ^4b , -S (O) ₂ X ¹ NR ^4a R ^4b , -X ¹ OC (O) NR ^4a R ^4b , -X ¹ NR ^4b C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a -C (O) NR ^4a R ^4b , -X ¹ OC (O) R ^4a , -X ¹ NR ^4a R ^4b , -OX ¹ OR ^4a , -OX ¹ NR ^4a R ^4b , -OX ¹ CO ₂ R ^4a , -OX ¹ CONR ^4a R ^4b , -N ^{1 to 4} selected from the group consisting of R ^4b -X ¹ OR ^4a , -NR ^4b -X ¹ NR ^4a R ^4b , -NR ^4b -X ¹ CO ₂ R ^4a , and -NR ^4b -X ¹ CONR ^4a R ^4b 5 or 6 membered aryl, heterocyclyl or aryl-C _1-2 alkyl, optionally substituted with 3 substituents; X ¹ and X ² are C _1-4 alkylene, C _2-4 alkenylene, respectively And R ^4a and R ^4b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C ₃ , and C _3-4 alkynylene. Independently selected from the group consisting of _-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl; R each ^4c, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl , C _2-8 alkynyl, aryl, heteroaryl, selected aryl -C _1-4 alkyl, and more independently aryloxy -C _1-4 group consisting of alkyl, and optionally R ^4a, of R ^4b and R ^4c Any two, when part of a common R ⁴ or R ^{4 ′} substituent, combine with the atoms to which each is attached to have 0 to 2 additional heteroatoms as ring members, Saturated or unsaturated, 4-9 membered monocyclic or bicyclic rings can be formed. In addition, R ^4a , R ^4b and R ^4c are each —OH, oxo, —R ^m , —OR ^m , —OC (O) NHR ^m , —OC (O) N (R ^m ) ₂ , —SH, -SR ^m -S (O) R ^m , -S (O) ₂ R ^m , -SO ₂ NH ₂ , -S (O) ₂ NHR ^m , -S (O) ₂ N (R ^m ) ₂ , -NHS (O) ₂ R ^m , -NR ^m S (O) ₂ R ^m , -C (O) NH ₂ , -C (O) NHR ^m , -C (O) N (R ^m ) ₂ , -C (O ) R ^m , -NHC (O) R ^m , -NR ^m C (O) R ^m , -NHC (O) NH ₂ , -NR ^m C (O) NH ₂ , -NR ^m C (O) NHR ^m , -NHC (O) NHR ^m , -NR ^m C (O) N (R ^m ) ₂ , -NHC (O) N (R ^m ) ₂ , -CO ₂ H, -CO ₂ R ^m , -NHCO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -NH ₂ , -NHR ^m , -N (R ^m ) ₂ , -NR ^m S (O) NH ₂ and -NR ^m S (O) ₂ It may be further substituted with 1 to 3 members selected from the group consisting of NHR ^m , wherein each R ^m is independently unsubstituted C _1-6 alkyl, benzyl, or each bonded. To form a saturated 4, 5, 6 or 7 membered ring with 0 to 2 additional heteroatoms as ring members.

Then with respect to formula (c), the symbols R ⁵ is _{^{-R 5a, -CO 2 R 5c,}} -CONR 5a R 5b, -C (O) R 5a, -C (= NR 5a) NR 5a R 5b, -C (= N ⁺ R ^5c R ^5c ) NR ^5a R ^5b , -C (= NR ^5a ) R ^5a , -C (= NR ^5a ) Y ¹ , -X ³ OR ^5a , -X ³ OC (O) R ^5a , -X ³ NR ^5a R ^5b , -X ³ SR ^5a , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^5a , -X ³ CONR ^5a R ^5b , -X ³ C (O) R ^5a , -X ³ OC (O) NR ^5a R ^5b , -X ³ NR ^5a C (O) R ^5a , -X ³ NR ^5b C (O) ₂ R ^5c , -X ³ NR ^5a C (O) NR ^5a R ^5b represents a member selected from the group consisting of -X ³ -C (= NR ^5a ) NR ^5a R ^5b , -Y ¹ , and -X ³ -Y ¹ , where Y ¹ is halogen, -OR ^5a , -OC (O) R ^5a, -NR ^5a R ^5b , -R ^5c , -SR ^5a , -CN, -NO ₂ , -CO ₂ R ^5a , -CONR ^5a R ^5b , -C (O) R ^5a ,- NR ^5b C (O) R ^5a , -NR ^5b C (O) ₂ R ^5C , -X ³ OR ^5a , -X ³ SR ^5a , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^5a , -X ³ CONR ^5a R ^5b , -X ³ C (O) R ^5a , -X ³ OC (O) NR ^5a R ^5b , -X ³ NR ^5b C (O) R ^5a , -X ³ NR ^5b C ( O) ₂ R ^5c , -X ³ NR ^5a -C (O) NR ^5a R ^5b , -X ³ OC (O) R ^5a , -X ³ NR ^5a R ^5b , -OX ³ OR ^5a ,- OX ³ NR ^5a R ^5b , -OX ³ CO ₂ R ^5a , -OX ³ CONR ^5a R ^5b , -NR ^5b -X ³ OR ^5a , -NR ^5b -X ³ NR ^5a R ^5b , -NR ^5b -X ³ CO 5 or 6-membered aryl or heteroaryl ring or aryl-C optionally substituted with 1 to 3 substituents selected from the group consisting of ₂ R ^5a , and —NR ^5b —X ³ CONR ^5a R ^5b _1-2 alkyl, wherein X ³ is a member independently selected from the group consisting of C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene; R ^5a and R ^5b are each Hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-, respectively Independently selected from the group consisting of C _1-4 alkyl, and aryloxy-C _1-4 alkyl; R ^5c is C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, respectively. Independently from the group consisting of alkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl And optionally any two of R ^5a , R ^5b, and R ^5c , when part of a common R ⁵ substituent, combine with the atom to which each is bonded to 0-1 Saturated 4, 5, 6 or 7 membered rings can be formed having as a ring member any of the following heteroatoms. In addition, R ^5a , R ^5b and R ^5c are -OH, -OR ⁿ , -OC (O) NHR ⁿ , -OC (O) N (R ⁿ ) ₂ , -SH, -SR ⁿ -S ( O) R ⁿ , -S (O) ₂ R ⁿ , -SO ₂ NH ₂ , -S (O) ₂ NHR ⁿ , -S (O) ₂ N (R ⁿ ) ₂ , -NHS (O) ₂ R ⁿ , -NR ⁿ S (O) ₂ R ⁿ , -C (O) NH ₂ , -C (O) NHR ⁿ , -C (O) N (R ⁿ ) ₂ , -C (O) R ⁿ , -NHC (O) R ⁿ , -NR ⁿ C (O) R ⁿ , -NHC (O) NH ₂ , -NR ⁿ C (O) NH ₂ , -NR ⁿ C (O) NHR ⁿ , -NHC (O) NHR ⁿ , -NR ⁿ C (O) N (R ⁿ ) ₂ , -NHC (O) N (R ⁿ ) ₂ , -CO ₂ H, -CO ₂ R ⁿ , -NHCO ₂ R ⁿ , -NR ⁿ CO ₂ From the group consisting of R ⁿ , -CN, -NO ₂ , -NH ₂ , -NHR ⁿ , -N (R ⁿ ) ₂ , -NR ⁿ S (O) NH ₂ and -NR ⁿ S (O) ₂ NHR ⁿ It may be further substituted with 1 to 3 members selected, wherein each R ⁿ is independently unsubstituted C _1-6 alkyl or benzyl.

もう一つの態様群において、Wは式(a)、(d)または(e)を有する。もう一つの態様群において、Wは式(c)を有する。特定の態様群において、nおよびmの少なくとも一つは1であり、R⁴およびR^4'はそれぞれ本発明の全範囲に関して提供される置換基のいずれであってもよい。一つの態様群において、R^4'は

から選択され、式中、波線は化合物の残部への結合点を示す。 Some specific embodiments of the invention have the above formula. In one embodiment group, W has the formula selected from the group consisting of (a), (d), (e) and (c):

In another group of embodiments, W has the formula (a), (d) or (e). In another group of embodiments, W has the formula (c). In certain embodiments, at least one of n and m is 1, and R ⁴ and R ^{4 ′} can each be any of the substituents provided for the full scope of the invention. In one embodiment group, R ^{4 ′} is

Where the wavy line indicates the point of attachment to the remainder of the compound.

からなる群より独立に選択され；R^4aはそれぞれ独立にHまたはC_1-4アルキルであり；R^4dはそれぞれ、H、OH、NH₂、N(CH₃)₂、CONH₂およびCON(CH₃)₂からなる群より独立に選択され；かつ波線は分子の残部への結合点を示す。 In another embodiment group, at least one of n and m is 1, and R ⁴ and R ^{4 ′} are each H, halogen, OR ^4a , C _1-4 alkyl, SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ N (R ^4a R ^4b ), NR ^4a R ^4b , C _1-4 alkyl OR ^4a , C _1-4 alkyl NR ^4a R ^4b , C _1-4 alkyl CO ₂ R ^4a , OC _1-4 alkyl OR ^4a , OC _1-4 alkyl N (R ^4a N ^4b ), N (R ^4a ) C _1-4 alkyl OR ^4b , N (R ^4a ) C _1-4 alkyl N (R ^4a R ^4b ), S (O) ₂ C _1-4 alkyl N (R ^4a R ^4b ),

Each independently selected from the group consisting of: R ^4a is independently H or C _1-4 alkyl; R ^4d is H, OH, NH ₂ , N (CH ₃ ) ₂ , CONH ₂ and CON (CH ₃ ) independently selected from the group consisting of ₂ ; and the wavy line indicates the point of attachment to the rest of the molecule.

からなる群より選択され；かつ波線は分子の残部への結合点を示す。 In another group of embodiments, at least one of n and m is 1, and R ⁴ and R ^{4 ′} are each

And the wavy line indicates the point of attachment to the rest of the molecule.

からなる群より選択され；nが0〜3の整数であり；R³はそれぞれ、ハロゲン、C_1-8アルキル、C_2-8アルケニル、C_2-8アルキニル、OR^3a、N(R^3a)₂、X⁰CO₂R^3a、X⁰CON(R^3a)₂、SO₂C_1-4、SO₂N(R^3a)₂からなる群より独立に選択され；R^3aはそれぞれ、H、C_1-8アルキル、C_2-8アルケニルおよびC_2-8アルキニルからなる群より独立に選択され；かつX⁰は結合またはC_1-8アルキレンであり；かつ破線はAへの結合点を示し、波線は分子の残部への結合点を示すものである。 In other embodiments, compounds of formula I are provided wherein R ^{4 ′} is attached to the ring at the para position relative to A. In other embodiments, compounds of formula I are provided wherein R ⁴ is attached to the ring at an ortho position relative to A. Within these embodiments, certain embodiments are provided wherein Y is a member selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl, pyrazolyl, triazolyl and imidazolyl, which may be substituted. Preferably, A represents benzene or a 6-membered heterocyclic ring containing 1 to 3 nitrogen atoms. One embodiment group is one in which A is selected from the group consisting of benzene, pyridine, pyridimidine, pyrazine, morpholin-3-one, piperazin-2-one, pyridin-2-one, piperidine, morpholine and piperazine. Yet another embodiment group is that A is

N is an integer from 0 to 3; R ³ is halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, OR ^3a , N (R ^3a ), respectively. ₂ , X ⁰ CO ₂ R ^3a , X ⁰ CON (R ^3a ) ₂ , SO ₂ C _1-4 , SO ₂ N (R ^3a ) ₂ are independently selected; R ^3a is H, C, respectively Independently selected from the group consisting of _1-8 alkyl, C _2-8 alkenyl and C _2-8 alkynyl; and X ⁰ is a bond or C _1-8 alkylene; and the dashed line indicates the point of attachment to A; The wavy line indicates the point of attachment to the rest of the molecule.

およびその薬学的に許容される塩を提供する。式(I)において、RはHおよびC_1-4アルキルからなる群より選択されるメンバーを表し；R¹はハロゲン、C_1-8アルキル、C_2-8アルケニルおよびC_2-8アルキニルからなる群より選択されるメンバーを表し；R²はH、C_1-8アルキル、-X-OR^2a、-X-SR^2a、-X-COR^2a、-X-CO₂R^2aおよび-X-N(R^2a)₂からなる群より選択されるメンバーを表し；ここでXはC_1-8アルキレンであり、かつR^2aはそれぞれ、HおよびC_1-8アルキルからなる群より独立に選択されるか、または任意で同じ窒素原子に結合している二つのR^2a基は化合して4-、5-、6-もしくは7-員環を形成する。記号R³はHおよびハロゲンからなる群より選択されるメンバーを表す。 In one aspect, the present invention provides a compound having the formula:

And pharmaceutically acceptable salts thereof. In formula (I), R represents a member selected from the group consisting of H and C _1-4 alkyl; R ¹ consists of halogen, C _1-8 alkyl, C _2-8 alkenyl and C _2-8 alkynyl Represents a member selected from the group; R ² is H, C _1-8 alkyl, —X—OR ^2a , —X—SR ^2a , —X—COR ^2a , —X—CO ₂ R ^2a and —XN (R ^2a ) represents a member selected from the group consisting of ₂ ; wherein X is C _1-8 alkylene and R ^2a is each independently selected from the group consisting of H and C _1-8 alkyl; Or, optionally, two R ^2a groups bonded to the same nitrogen atom combine to form a 4-, 5-, 6-, or 7-membered ring. The symbol R ³ represents a member selected from the group consisting of H and halogen.

The letter W represents a moiety having a formula selected from (a), (b), and (c):

With respect to formula (b), the symbols Z ¹ , Z ² , and Z ³ each independently represent N, C, or CH, provided that ^{two of} Z ¹ , Z ² , and Z ³ are other than N.

For formulas (a) and (b), the subscript n is an integer from 0 to 3 and the subscript m is an integer from 0 to 1. The symbol R ⁴ represents, at each occurrence, halogen, -OR ^4a , -OC (O) R ^4a , -NR ^4a R ^4b , -SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R ^4b , -R ^4c , -CN, -NO ₂ , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , -OC (O) NR ^4a R ^4b , -NR ^4b C (O) R ^4a , -NR ^4b C (O) ₂ R ^4c , -NR ^4a -C (O) NR ^4a R ^4b , -X ¹ OR ^4a , -X ¹ OC (O) R ^4a , -X ¹ NR ^4a R ^4b , -X ¹ SR ^4a , -X ¹ S (O) R ^4a , -X ¹ S (O) ₂ R ^4a , -X ¹ CN, -X ¹ NO ₂ , -X ¹ CO ₂ R ^4a , -OX ¹ CO ₂ R ^4a , -X ¹ CONR ^4a R ^4b , -OX ¹ CONR ^4a R ^4b , -X ¹ C (O) R ^4a , -OX ¹ NR ^4a R ^4b , -S (O ) X ¹ NR ^4a R ^4b , -S (O) ₂ X ¹ NR ^4a R ^4b , -X ¹ OC (O) NR ^4a R ^4b , -X ¹ NR ^4a C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a C (O) NR ^4a R ^4b , -Y, -X ¹ -Y, -OY, -NR ^4a Y, -SY, -S (O) Y and- Represents a member selected from the group consisting of S (O) ₂ Y. Similarly, R ^{4 ′} is -C (= NH) R ^4a , -C (= NR ^4c ) R ^4a , -C (= NH) NR ^4a R ^4b , -C (= NR ^4c ) NR ^4a R ^4b ,- C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b , -X ² -C (= NH) NR ^4a R ^4b , -X ² -C (= NR ^4c ) NR ^4a R ^4b , -X ² -C ( = N ⁺ R ^4c R ^4c ) NR ^4a R ^4b and -C (= NR ^4a ) NR ^4a represents a member selected from the group consisting of -Y, where Y is halogen, oxo, -OR ^4a , -OC ( O) R ^4a , -NR ^4a R ^4b , -R ^4c , -SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R ^4b , -CN, -NO ₂ , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , -NR ^4b C (O) R ^4a , -NR ^4b C (O) ₂ R ^4c , -X ¹ R ^4a , -X ¹ OR ^4a , -X ¹ SR ^4a , -X ¹ S (O) R ^4a , -X ¹ S (O) ₂ R ^4a , -X ¹ CN, -X ¹ NO ₂ , -X ¹ CO ₂ R ^4a , -X ¹ CONR ^4a R ^4b , -X ¹ C (O) R ^4a , -OX ¹ NR ^4a R ^4b , -S (O) X ¹ NR ^4a R ^4b , -S (O) ₂ X ¹ NR ^4a R ^4b , -X ¹ OC (O) NR ^4a R ^4b , -X ¹ NR ^4b C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a -C (O) NR ^4a R ^4b , -X ¹ OC (O) R ^4a , -X ¹ NR ^4a R ^4b , -OX ¹ OR ^4a , -OX ¹ NR ^4a R ^4b , -OX ¹ CO ₂ R ^4a , -OX ¹ CONR ^4a R ^4b , -N ^{1 to 4} selected from the group consisting of R ^4b -X ¹ OR ^4a , -NR ^4b -X ¹ NR ^4a R ^4b , -NR ^4b -X ¹ CO ₂ R ^4a , and -NR ^4b -X ¹ CONR ^4a R ^4b 5 or 6 membered aryl, heterocyclyl or aryl-C _1-2 alkyl, optionally substituted with 3 substituents; X ¹ and X ² are C _1-4 alkylene, C _2-4 alkenylene, respectively And R ^4a and R ^4b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C ₃ , and C _3-4 alkynylene. Independently selected from the group consisting of _-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl; R each ^4c, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl , C _2-8 alkynyl, aryl, heteroaryl, selected aryl -C _1-4 alkyl, and more independently aryloxy -C _1-4 group consisting of alkyl, and optionally R ^4a, of R ^4b and R ^4c Any two, when part of a common R ⁴ or R ^{4 ′} substituent, combine with the atoms to which each is attached to have 0 to 2 additional heteroatoms as ring members, Saturated or unsaturated, 4-9 membered monocyclic or bicyclic rings can be formed. In addition, R ^4a , R ^4b and R ^4c are each —OH, oxo, —R ^m , —OR ^m , —OC (O) NHR ^m , —OC (O) N (R ^m ) ₂ , —SH, -SR ^m -S (O) R ^m , -S (O) ₂ R ^m , -SO ₂ NH ₂ , -S (O) ₂ NHR ^m , -S (O) ₂ N (R ^m ) ₂ , -NHS (O) ₂ R ^m , -NR ^m S (O) ₂ R ^m , -C (O) NH ₂ , -C (O) NHR ^m , -C (O) N (R ^m ) ₂ , -C (O ) R ^m , -NHC (O) R ^m , -NR ^m C (O) R ^m , -NHC (O) NH ₂ , -NR ^m C (O) NH ₂ , -NR ^m C (O) NHR ^m , -NHC (O) NHR ^m , -NR ^m C (O) N (R ^m ) ₂ , -NHC (O) N (R ^m ) ₂ , -CO ₂ H, -CO ₂ R ^m , -NHCO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -NH ₂ , -NHR ^m , -N (R ^m ) ₂ , -NR ^m S (O) NH ₂ and -NR ^m S (O) ₂ It may be further substituted with 1 to 3 members selected from the group consisting of NHR ^m , wherein each R ^m is independently unsubstituted C _1-6 alkyl, benzyl, or each bonded. To form a saturated 4, 5, 6 or 7 membered ring with 0 to 2 additional heteroatoms as ring members.

Next, regarding the formula (c), the symbol R ⁵ is -R ^5a , -CO ₂ R ^5c , -CONR ^5a R ^5b , -C (O) R ^5a , -C (= NH) NR ^5a R ^5b , -C ( = NR ^5c ) NR ^5a R ^5b , -C (= N ⁺ R ^5c R ^5c ) NR ^5a R ^5b , -C (= NR ^5a ) R ^5a , -C (= NR ^5a ) Y ¹ , -X ³ OR ^5a , -X ³ OC (O) R ^5a , -X ³ NR ^5a R ^5b , -X ³ SR ^5a , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^5a , -X ³ CONR ^5a R ^5b , -X ³ C (O) R ^5a , -X ³ OC (O) NR ^5a R ^5b , -X ³ NR ^5a C (O) R ^5a , -X ³ NR ^5b C (O) ₂ R ^5c ,- Represents a member selected from the group consisting of X ³ NR ^5a C (O) NR ^5a R ^5b , -X ³ -C (= NR ^5a ) NR ^5a R ^5b , -Y ¹ , and -X ³ -Y ¹ ; Where Y ¹ is halogen, -OR ^5a , -OC (O) R ^5a, -NR ^5a R ^5b , -R ^5c , -SR ^5a , -CN, -NO ₂ , -CO ₂ R ^5a , -CONR ^5a R ^5b , -C (O) R ^5a , -NR ^5b C (O) R ^5a , -NR ^5b C (O) ₂ R ^5C , -X ³ OR ^5a , -X ³ SR ^5a , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^5a , -X ³ CONR ^5a R ^5b , -X ³ C (O) R ^5a , -X ³ OC (O) NR ^5a R ^5b , -X ³ NR ^5b C (O ) R ^5a , -X ³ NR ^5b C (O) ₂ R ^5c , -X ³ NR ^5a -C (O) NR ^5a R ^5b , -X ³ OC (O) R ^5a , -X ³ NR ^5a R ^{5 b} , -OX ³ OR ^5a , -OX ³ NR ^5a R ^5b , -OX ³ CO ₂ R ^5a , -OX ³ CONR ^5a R ^5b , -NR ^5b -X ³ OR ^5a , -NR ^5b -X ³ NR ^5a R Optionally substituted by 1 to 3 substituents selected from the group consisting of ^5b , -NR ^5b -X ³ CO ₂ R ^5a , and -NR ^5b -X ³ CONR ^5a R ^5b An aryl or heteroaryl ring or aryl-C _1-2 alkyl, wherein X ³ are each independently selected from the group consisting of C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene; R ^5a and R ^5b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, selected aryl -C _1-4 alkyl, and more independently aryloxy -C _1-4 group consisting of alkyl; R ^5c each, C _1-8 alkyl, C _1-8 Haroaruki , C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl -C _1-4 alkyl, and aryloxy -C _1-4 alkyl Independently selected from the group consisting of: and optionally any two of R ^5a , R ^5b, and R ^5c , when part of a common R ⁵ substituent, are each combined with the atom to which they are attached. Can form saturated 4, 5, 6 or 7 membered rings with 0-1 additional heteroatoms as ring members. In addition, R ^5a , R ^5b and R ^5c are -OH, -OR ⁿ , -OC (O) NHR ⁿ , -OC (O) N (R ⁿ ) ₂ , -SH, -SR ⁿ -S ( O) R ⁿ , -S (O) ₂ R ⁿ , -SO ₂ NH ₂ , -S (O) ₂ NHR ⁿ , -S (O) ₂ N (R ⁿ ) ₂ , -NHS (O) ₂ R ⁿ , -NR ⁿ S (O) ₂ R ⁿ , -C (O) NH ₂ , -C (O) NHR ⁿ , -C (O) N (R ⁿ ) ₂ , -C (O) R ⁿ , -NHC (O) R ⁿ , -NR ⁿ C (O) R ⁿ , -NHC (O) NH ₂ , -NR ⁿ C (O) NH ₂ , -NR ⁿ C (O) NHR ⁿ , -NHC (O) NHR ⁿ , -NR ⁿ C (O) N (R ⁿ ) ₂ , -NHC (O) N (R ⁿ ) ₂ , -CO ₂ H, -CO ₂ R ⁿ , -NHCO ₂ R ⁿ , -NR ⁿ CO ₂ From the group consisting of R ⁿ , -CN, -NO ₂ , -NH ₂ , -NHR ⁿ , -N (R ⁿ ) ₂ , -NR ⁿ S (O) NH ₂ and -NR ⁿ S (O) ₂ NHR ⁿ It may be further substituted with 1 to 3 members selected, wherein each R ⁿ is independently unsubstituted C _1-6 alkyl or benzyl.

から選択され、式中、波線は化合物の残部への結合点を示す。より好ましくは、R^4'は環Aの結合に対してパラの位置でフェニル環に結合している。 Some other embodiments of the present invention have the formulas described above. In one embodiment group, W has the formula (a). In another embodiment group, the subscript m is 1. In another group of embodiments, R ^{4 ′} can be any of the substituents provided for the full scope of the invention. In one embodiment group, R ^{4 ′} is

Where the wavy line indicates the point of attachment to the remainder of the compound. More preferably, R ^{4 ′} is attached to the phenyl ring at a position para to the attachment of ring A.

およびその薬学的に許容される塩を提供する。式(I)において、Aは、ハロゲン、オキソ、R^A、-OR^A、N(R^A)₂、CO₂R^A、CON(R^A)₂、S(O)₂R^A、S(O)₂N(R^A)₂、X¹OR^A、X¹CO₂R^A、X¹CON(R^A)₂、X¹N(R^A)₂から選択される0〜4個の置換基を有する、1〜4個の窒素、酸素、または硫黄原子を含む5員複素環を表し、ここでR^Aはそれぞれ、H、C_1-8アルキル、C_2-8アルケニル、C_2-8アルキニルから独立に選択されるか、または任意で同じ原子に結合している二つのR^Aは化合して3-、4-、5-、6-もしくは7-員環を形成する。一つの態様群において、Aはイソキサゾール、イソチアゾール、ピラゾール、イミダゾール、オキサゾール、チアゾール、イソキサゾリン、ピラゾリン、イミダゾリン、1,2,3-トリアゾール、1,2,4-トリアゾール、1,3,4-オキサジアゾール、1,3,4-チアジアゾール、1,2,4-オキサジアゾール、1,2,4-チアジアゾール、ピラゾル-5-オン、ピロリジン-2,5-ジオン、イミダゾリジン-2,4-ジオン、ピロリジン、ピロール、フランおよびチオフェンからなる群より選択される。RはHおよびC_1-4アルキルからなる群より選択されるメンバーを表し；R¹はハロゲン、C_1-8アルキル、C_2-8アルケニルおよびC_2-8アルキニルからなる群より選択されるメンバーを表し；R²はH、C_1-8アルキル、-X-OR^2a、-X-SR^2a、-X-COR^2a、-X-CO₂R^2aおよび-X-N(R^2a)₂からなる群より選択されるメンバーを表し；ここでXはC_1-8アルキレンであり、かつR^2aはそれぞれ、HおよびC_1-8アルキルからなる群より独立に選択されるか、または任意で同じ窒素原子に結合している二つのR^2a基は化合して4-、5-、6-もしくは7-員環を形成する。 In one aspect, the present invention provides a compound having the formula:

And pharmaceutically acceptable salts thereof. In the formula (I), A is halogen, oxo, R ^A , —OR ^A , N (R ^A ) ₂ , CO ₂ R ^A , CON (R ^A ) ₂ , S (O) ₂ R ^A , S (O ) 0 to 4 substituents selected from ₂ N (R ^A ) ₂ , X ¹ OR ^A , X ¹ CO ₂ R ^A , X ¹ CON (R ^A ) ₂ , X ¹ N (R ^A ) ₂ And represents a 5-membered heterocycle containing 1 to 4 nitrogen, oxygen, or sulfur atoms, where R ^A is from H, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, respectively. Two R ^A , independently selected or optionally attached to the same atom, combine to form a 3-, 4-, 5-, 6- or 7-membered ring. In one embodiment group A is isoxazole, isothiazole, pyrazole, imidazole, oxazole, thiazole, isoxazoline, pyrazoline, imidazoline, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxa. Diazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, pyrazol-5-one, pyrrolidine-2,5-dione, imidazolidine-2,4- Selected from the group consisting of dione, pyrrolidine, pyrrole, furan and thiophene. R represents a member selected from the group consisting of H and C _1-4 alkyl; R ¹ is a member selected from the group consisting of halogen, C _1-8 alkyl, C _2-8 alkenyl and C _2-8 alkynyl R ² represents H, C _1-8 alkyl, —X—OR ^2a , —X—SR ^2a , —X—COR ^2a , —X—CO ₂ R ^2a and —XN (R ^2a ) ₂ Wherein X is C _1-8 alkylene and R ^2a is each independently selected from the group consisting of H and C _1-8 alkyl, or optionally the same nitrogen atom The two R ^2a groups attached to are combined to form a 4-, 5-, 6- or 7-membered ring.

The letter W represents a moiety having a formula selected from (a), (b), and (c):

With respect to formula (b), the symbols Z ¹ , Z ² , and Z ³ each independently represent N, C, or CH, provided that ^{two of} Z ¹ , Z ² , and Z ³ are other than N.

For formulas (a) and (b), the subscript n is an integer from 0 to 3 and the subscript m is an integer from 0 to 1. The symbol R ⁴ represents, at each occurrence, halogen, -OR ^4a , -OC (O) R ^4a , -NR ^4a R ^4b , -SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R ^4b , -R ^4c , -CN, -NO ₂ , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , -OC (O) NR ^4a R ^4b , -NR ^4b C (O) R ^4a , -NR ^4b C (O) ₂ R ^4c , -NR ^4a -C (O) NR ^4a R ^4b , -X ¹ OR ^4a , -X ¹ OC (O) R ^4a , -X ¹ NR ^4a R ^4b , -X ¹ SR ^4a , -X ¹ S (O) R ^4a , -X ¹ S (O) ₂ R ^4a , -X ¹ CN, -X ¹ NO ₂ , -X ¹ CO ₂ R ^4a , -OX ¹ CO ₂ R ^4a , -X ¹ CONR ^4a R ^4b , -OX ¹ CONR ^4a R ^4b , -X ¹ C (O) R ^4a , -OX ¹ NR ^4a R ^4b , -S (O ) X ¹ NR ^4a R ^4b , -S (O) ₂ X ¹ NR ^4a R ^4b , -X ¹ OC (O) NR ^4a R ^4b , -X ¹ NR ^4a C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a C (O) NR ^4a R ^4b , -Y, -X ¹ -Y, -OY, -NR ^4a Y, -SY, -S (O) Y and- Represents a member selected from the group consisting of S (O) ₂ Y. Similarly, R ^{4 ′} is -C (= NH) R ^4a , -C (= NR ^4c ) R ^4a , -C (= NH) NR ^4a R ^4b , -C (= NR ^4c ) NR ^4a R ^4b ,- C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b , -X ² -C (= NH) NR ^4a R ^4b , -X ² -C (= NR ^4c ) NR ^4a R ^4b , -X ² -C ( = N ⁺ R ^4c R ^4c ) NR ^4a R ^4b and -C (= NR ^4a ) NR ^4a represents a member selected from the group consisting of -Y, where Y is halogen, oxo, -OR ^4a , -OC ( O) R ^4a , -NR ^4a R ^4b , -R ^4c , -SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R ^4b , -CN, -NO ₂ , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , -NR ^4b C (O) R ^4a , -NR ^4b C (O) ₂ R ^4c , -X ¹ R ^4a , -X ¹ OR ^4a , -X ¹ SR ^4a , -X ¹ S (O) R ^4a , -X ¹ S (O) ₂ R ^4a , -X ¹ CN, -X ¹ NO ₂ , -X ¹ CO ₂ R ^4a , -X ¹ CONR ^4a R ^4b , -X ¹ C (O) R ^4a , -OX ¹ NR ^4a R ^4b , -S (O) X ¹ NR ^4a R ^4b , -S (O) ₂ X ¹ NR ^4a R ^4b , -X ¹ OC (O) NR ^4a R ^4b , -X ¹ NR ^4b C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a -C (O) NR ^4a R ^4b , -X ¹ OC (O) R ^4a , -X ¹ NR ^4a R ^4b , -OX ¹ OR ^4a , -OX ¹ NR ^4a R ^4b , -OX ¹ CO ₂ R ^4a , -OX ¹ CONR ^4a R ^4b , -N ¹ selected from the group consisting of R ^4b -X ¹ OR ^4a , -NR ^4b -X ¹ NR ^4a R ^4b , -NR ^4b -X ¹ CO ₂ R ^4a , and -NR ^4b -X ¹ CONR ^4a R ^4bb 5 or 6 membered aryl, heterocyclyl or aryl-C _1-2 alkyl, optionally substituted with 3 substituents; X ¹ and X ² are C _1-4 alkylene, C _2-4 alkenylene, respectively And R ^4a and R ^4b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C ₃ , and C _3-4 alkynylene. Independently selected from the group consisting of _-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl; R ^4c is C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, respectively. R, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl, and optionally selected from R ^4a , R ^4b and R ^4c Any two of which, when part of a common R ⁴ or R ^{4 ′} substituent, combine with the atom to which each is attached to have 0 to 2 additional heteroatoms as ring members , Saturated or unsaturated, 4-9 membered monocyclic or bicyclic rings can be formed. In addition, R ^4a , R ^4b and R ^4c are each —OH, oxo, —R ^m , —OR ^m , —OC (O) NHR ^m , —OC (O) N (R ^m ) ₂ , —SH, -SR ^m -S (O) R ^m , -S (O) ₂ R ^m , -SO ₂ NH ₂ , -S (O) ₂ NHR ^m , -S (O) ₂ N (R ^m ) ₂ , -NHS (O) ₂ R ^m , -NR ^m S (O) ₂ R ^m , -C (O) NH ₂ , -C (O) NHR ^m , -C (O) N (R ^m ) ₂ , -C (O ) R ^m , -NHC (O) R ^m , -NR ^m C (O) R ^m , -NHC (O) NH ₂ , -NR ^m C (O) NH ₂ , -NR ^m C (O) NHR ^m , -NHC (O) NHR ^m , -NR ^m C (O) N (R ^m ) ₂ , -NHC (O) N (R ^m ) ₂ , -CO ₂ H, -CO ₂ R ^m , -NHCO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -NH ₂ , -NHR ^m , -N (R ^m ) ₂ , -NR ^m S (O) NH ₂ and -NR ^m S (O) ₂ It may be further substituted with 1 to 3 members selected from the group consisting of NHR ^m , wherein each R ^m is independently unsubstituted C _1-6 alkyl, benzyl, or each bonded. To form a saturated 4, 5, 6 or 7 membered ring with 0 to 2 additional heteroatoms as ring members.

Next, regarding the formula (c), the symbol R ⁵ is -R ^5a , -CO ₂ R ^5c , -CONR ^5a R ^5b , -C (O) R ^5a , -C (= NH) NR ^5a R ^5b , -C ( = NR ^5c ) NR ^5a R ^5b , -C (= N ⁺ R ^5c R ^5c ) NR ^5a R ^5b , -C (= NR ^5a ) R ^5a , -C (= NR ^5a ) Y ¹ , -X ³ OR ^5a , -X ³ OC (O) R ^5a , -X ³ NR ^5a R ^5b , -X ³ SR ^5a , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^5a , -X ³ CONR ^5a R ^5b , -X ³ C (O) R ^5a , -X ³ OC (O) NR ^5a R ^5b , -X ³ NR ^5a C (O) R ^5a , -X ³ NR ^5b C (O) ₂ R ^5c ,- Represents a member selected from the group consisting of X ³ NR ^5a C (O) NR ^5a R ^5b , -X ³ -C (= NR ^5a ) NR ^5a R ^5b , -Y ¹ , and -X ³ -Y ¹ ; Where Y ¹ is halogen, -OR ^5a , -OC (O) R ^5a, -NR ^5a R ^5b , -R ^5c , -SR ^5a , -CN, -NO ₂ , -CO ₂ R ^5a , -CONR ^5a R ^5b , -C (O) R ^5a , -NR ^5b C (O) R ^5a , -NR ^5b C (O) ₂ R ^5C , -X ³ OR ^5a , -X ³ SR ^5a , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^5a , -X ³ CONR ^5a R ^5b , -X ³ C (O) R ^5a , -X ³ OC (O) NR ^5a R ^5b , -X ³ NR ^5b C (O ) R ^5a , -X ³ NR ^5b C (O) ₂ R ^5c , -X ³ NR ^5a -C (O) NR ^5a R ^5b , -X ³ OC (O) R ^5a , -X ³ NR ^5a R ^{5 b} , -OX ³ OR ^5a , -OX ³ NR ^5a R ^5b , -OX ³ CO ₂ R ^5a , -OX ³ CONR ^5a R ^5b , -NR ^5b -X ³ OR ^5a , -NR ^5b -X ³ NR ^5a R Optionally substituted by 1 to 3 substituents selected from the group consisting of ^5b , -NR ^5b -X ³ CO ₂ R ^5a , and -NR ^5b -X ³ CONR ^5a R ^5b An aryl or heteroaryl ring or aryl-C _1-2 alkyl, wherein X ³ are each independently selected from the group consisting of C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene; R ^5a and R ^5b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, selected aryl -C _1-4 alkyl, and more independently aryloxy -C _1-4 group consisting of alkyl; R ^5c each, C _1-8 alkyl, C _1-8 Haroaruki , C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl -C _1-4 alkyl, and aryloxy -C _1-4 alkyl Independently selected from the group consisting of: and optionally any two of R ^5a , R ^5b, and R ^5c , when part of a common R ⁵ substituent, are each combined with the atom to which they are attached. Can form saturated 4, 5, 6 or 7 membered rings with 0-1 additional heteroatoms as ring members. In addition, R ^5a , R ^5b and R ^5c are -OH, -OR ⁿ , -OC (O) NHR ⁿ , -OC (O) N (R ⁿ ) ₂ , -SH, -SR ⁿ -S ( O) R ⁿ , -S (O) ₂ R ⁿ , -SO ₂ NH ₂ , -S (O) ₂ NHR ⁿ , -S (O) ₂ N (R ⁿ ) ₂ , -NHS (O) ₂ R ⁿ , -NR ⁿ S (O) ₂ R ⁿ , -C (O) NH ₂ , -C (O) NHR ⁿ , -C (O) N (R ⁿ ) ₂ , -C (O) R ⁿ , -NHC (O) R ⁿ , -NR ⁿ C (O) R ⁿ , -NHC (O) NH ₂ , -NR ⁿ C (O) NH ₂ , -NR ⁿ C (O) NHR ⁿ , -NHC (O) NHR ⁿ , -NR ⁿ C (O) N (R ⁿ ) ₂ , -NHC (O) N (R ⁿ ) ₂ , -CO ₂ H, -CO ₂ R ⁿ , -NHCO ₂ R ⁿ , -NR ⁿ CO ₂ From the group consisting of R ⁿ , -CN, -NO ₂ , -NH ₂ , -NHR ⁿ , -N (R ⁿ ) ₂ , -NR ⁿ S (O) NH ₂ and -NR ⁿ S (O) ₂ NHR ⁿ It may be further substituted with 1 to 3 members selected, wherein each R ⁿ is independently unsubstituted C _1-6 alkyl or benzyl.

からなる群より選択され；R³はそれぞれ、ハロゲン、C_1-8アルキル、C_2-8アルケニル、C_2-8アルキニル、OR^3a、N(R^3a)₂、X⁰CO₂R^3a、X⁰CON(R^3a)₂、SO₂C_1-4、SO₂N(R^3a)₂からなる群より独立に選択され；R^3aはそれぞれ、H、C_1-8アルキル、C_2-8アルケニルおよびC_2-8アルキニルからなる群より独立に選択され；かつX⁰は結合またはC_1-8アルキレンであり；かつ破線はAへの結合点を示し、波線は分子の残部への結合点を示す。もう一つの態様群において、Wは式(a)を有する。もう一つの態様群において、下付き文字mは1である。もう一つの態様群において、R^4'は本発明の全範囲に関して提供される置換基のいずれであってもよい。一つの態様群において、R^4'は

から選択され、式中、波線は化合物の残部への結合点を示す。より好ましくは、R^4'は環Aの結合に対してパラの位置でフェニル環に結合している。もう一つの態様群において、下付き文字nは0〜1の整数である。もう一つの態様群において、nは1であり；R⁴はAに対してオルトの位置でフェニル環に結合しており、R^4'はAに対してパラの位置でフェニル環に結合している。一つの態様群において、R⁴はハロゲン、-OR^4a、-NR^4aR^4b、-SR^4a、-Y、-X¹-Y、-O-Y、-NR^4aYおよび-SYからなる群より選択される。 Some other embodiments of the present invention have the formulas described above. In one embodiment group, A is

R ³ is selected from the group consisting of: halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, OR ^3a , N (R ^3a ) ₂ , X ⁰ CO ₂ R ^3a , X ⁰ CON (R ^3a ) ₂ , SO ₂ C _1-4 , SO ₂ N (R ^3a ) ₂ is independently selected; R ^3a is H, C _1-8 alkyl, C _2-8 alkenyl, respectively. And C _2-8 alkynyl; and X ⁰ is a bond or C _1-8 alkylene; and the dashed line indicates the point of attachment to A and the wavy line indicates the point of attachment to the rest of the molecule. Show. In another group of embodiments, W has the formula (a). In another embodiment group, the subscript m is 1. In another group of embodiments, R ^{4 ′} can be any of the substituents provided for the full scope of the invention. In one embodiment group, R ^{4 ′} is

Where the wavy line indicates the point of attachment to the remainder of the compound. More preferably, R ^{4 ′} is attached to the phenyl ring at a position para to the attachment of ring A. In another embodiment group, the subscript n is an integer from 0 to 1. In another group of embodiments, n is 1; R ⁴ is attached to the phenyl ring at the ortho position relative to A, and R ^{4 ′} is attached to the phenyl ring at the para position relative to A. Yes. In one embodiment group, R ⁴ is selected from the group consisting of halogen, -OR ^4a , -NR ^4a R ^4b , -SR ^4a , -Y, -X ¹ -Y, -OY, -NR ^4a Y and -SY. The

からなる群より選択され、式中、波線は化合物の残部への結合点を示す。 In another group of embodiments, m is 0 or 1, n is 0, 1 or 2, and at least one R ⁴ is

Wherein the wavy line indicates the point of attachment to the remainder of the compound.

In another embodiment group, m is 0 or 1; n is 0, 1 or 2; and at least one R ⁴ is -Y, -X ¹ -Y, -OY, -NR ^4a Y,- SY, -S (O) Y and -S (O) ₂ Y are selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl and pyrazolyl, substituted You may be a member. More preferably, R ⁴ is selected from the group consisting of -Y, -X ¹ -Y, -OY and -NR ^4a Y, wherein Y is selected from the group consisting of phenyl, benzyl, pyridyl and pyridylmethyl. A member that may be substituted. More preferably, the optional substituent is halogen, -OR ^4a , -NR ^4a R ^4b , -R ^4c , -SR ^4a , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , It is an embodiment selected from the group consisting of -X ¹ OR ^4a and -X ¹ NR ^4a R ^4b .

In other embodiments, compounds of formula I are provided wherein R ² is present and the carbon attached to R ² has the R configuration. Other embodiments are provided wherein R ³ is other than H and the carbon attached to R ³ has the R configuration.

In another embodiment, there is provided a compound of formula I, wherein W has formula (b). Within this group, certain embodiments are provided wherein Z ¹ is N. Another embodiment is provided wherein Z ² is N. Another embodiment is provided wherein Z ³ is N.

から選択され、式中、波線は化合物の残部への結合点を示す。より好ましくは、R^4'は環Aの結合に対してパラの位置でピリジル環に結合している。もう一つの態様群において、下付き文字nは0〜1の整数である。もう一つの態様群において、nは1であり；R⁴はAに対してオルトの位置でピリジル環に結合しており、R^4'はAに対してパラの位置でピリジル環に結合している。一つの態様群において、R⁴はハロゲン、-OR^4a、-NR^4aR^4b、-SR^4a、-Y、-X¹-Y、-O-Y、-NR^4aYおよび-SYからなる群より選択される。 In another embodiment group, the subscript m is 1. In another group of embodiments, R ^{4 ′} can be any of the substituents provided for the full scope of the invention. In one embodiment group, R ^{4 ′} is

Where the wavy line indicates the point of attachment to the remainder of the compound. More preferably, R ^{4 ′} is attached to the pyridyl ring at a position para to the attachment of ring A. In another embodiment group, the subscript n is an integer from 0 to 1. In another group of embodiments, n is 1; R ⁴ is attached to the pyridyl ring at the ortho position relative to A and R ^{4 ′} is attached to the pyridyl ring at the para position relative to A. Yes. In one embodiment group, R ⁴ is selected from the group consisting of halogen, -OR ^4a , -NR ^4a R ^4b , -SR ^4a , -Y, -X ¹ -Y, -OY, -NR ^4a Y and -SY. The

からなる群より選択され、式中、波線は化合物の残部への結合点を示す。 In another group of embodiments, m is 0 or 1, n is 0, 1 or 2, and at least one R ⁴ is

Wherein the wavy line indicates the point of attachment to the remainder of the compound.

In another embodiment group, m is 0 or 1; n is 0, 1 or 2; and at least one R ⁴ is -Y, -X ¹ -Y, -OY, -NR ^4a Y,- SY, -S (O) Y and -S (O) ₂ Y are selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl and pyrazolyl, substituted You may be a member. More preferably, R ⁴ is selected from the group consisting of -Y, -X ¹ -Y, -OY and -NR ^4a Y, wherein Y is selected from the group consisting of phenyl, benzyl, pyridyl and pyridylmethyl. A member that may be substituted. More preferably, the optional substituent is halogen, -OR ^4a , -NR ^4a R ^4b , -R ^4c , -SR ^4a , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , It is an embodiment selected from the group consisting of -X ¹ OR ^4a and -X ¹ NR ^4a R ^4b .

In another embodiment, there is provided a compound of formula I, wherein W has formula (c). Other embodiments are provided wherein Y ¹ is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridyl. R ⁵ is selected from the group consisting of -R ^5a , -C (= NH) NR ^5a R ^5b , -C (= NH) R ^5a , -C (= NH) Y ¹ and -X ³ -Y ¹ Other aspects are provided.

およびその薬学的に許容される塩を提供する。式(I)において、RはHおよびC_1-4アルキルからなる群より選択されるメンバーを表し；R¹はハロゲン、C_1-8アルキル、C_2-8アルケニルおよびC_2-8アルキニルからなる群より選択されるメンバーを表し；R²はH、C_1-8アルキル、-X-OR^2a、-X-SR^2a、-X-COR^2a、-X-CO₂R^2aおよび-X-N(R^2a)₂からなる群より選択されるメンバーを表し；ここでXはC_1-8アルキレンであり、かつR^2aはそれぞれ、HおよびC_1-8アルキルからなる群より独立に選択されるか、または任意で同じ窒素原子に結合している二つのR^2a基は化合して4-、5-、6-もしくは7-員環を形成する。式(I)における破線は、任意の結合は一つだけ存在するとの認識のもとで、それぞれ独立に任意の結合を表す。記号R³はHおよびC_1-4アルキルからなる群より選択されるメンバーを表すか；またはR³が存在する場合には結合することになる環に炭素-炭素二重結合がある場合は存在しない。R²が存在するか、またはR³が存在して、H以外である態様について、好ましい態様群は、R²またはR³が結合している炭素が(R)立体化学配置を有するものである。 In one aspect, the present invention provides a compound having the formula:

And pharmaceutically acceptable salts thereof. In formula (I), R represents a member selected from the group consisting of H and C _1-4 alkyl; R ¹ consists of halogen, C _1-8 alkyl, C _2-8 alkenyl and C _2-8 alkynyl Represents a member selected from the group; R ² is H, C _1-8 alkyl, —X—OR ^2a , —X—SR ^2a , —X—COR ^2a , —X—CO ₂ R ^2a and —XN (R ^2a ) represents a member selected from the group consisting of ₂ ; wherein X is C _1-8 alkylene and R ^2a is each independently selected from the group consisting of H and C _1-8 alkyl; Or, optionally, two R ^2a groups bonded to the same nitrogen atom combine to form a 4-, 5-, 6-, or 7-membered ring. The broken line in formula (I) represents an arbitrary bond independently with the recognition that only one arbitrary bond exists. The symbol R ³ represents a member selected from the group consisting of H and C _1-4 alkyl; or present if there is a carbon-carbon double bond in the ring to which it will be attached if R ³ is present do not do. For embodiments in which R ² is present or R ³ is present and is other than H, preferred embodiments are those in which the carbon to which R ² or R ³ is attached has the (R) stereochemical configuration .

The letter W represents a moiety having a formula selected from (a), (b), and (c):

With respect to formula (b), the symbols Z ¹ , Z ² , and Z ³ each independently represent N, C, or CH, provided that ^{two of} Z ¹ , Z ² , and Z ³ are other than N. The pyridyl nitrogen can be para (Z ¹ (4-pyridyl)), meta (Z ² (3-pyridyl)) or ortho (Z ³ (2-pyridyl)) relative to the bond of the isoxazole or isoxazoline ring.

For formulas (a) and (b), the subscript n is an integer from 0 to 3 and the subscript m is an integer from 0 to 1. The symbol R ⁴ represents, at each occurrence, halogen, -OR ^4a , -OC (O) R ^4a , -NR ^4a R ^4b , -SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R ^4b , -R ^4c , -CN, -NO ₂ , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , -OC (O) NR ^4a R ^4b , -NR ^4b C (O) R ^4a , -NR ^4b C (O) ₂ R ^4c , -NR ^4a -C (O) NR ^4a R ^4b , -X ¹ OR ^4a , -X ¹ OC (O) R ^4a , -X ¹ NR ^4a R ^4b , -X ¹ SR ^4a , -X ¹ S (O) R ^4a , -X ¹ S (O) ₂ R ^4a , -X ¹ CN, -X ¹ NO ₂ , -X ¹ CO ₂ R ^4a , -OX ¹ CO ₂ R ^4a , -X ¹ CONR ^4a R ^4b , -OX ¹ CONR ^4a R ^4b , -X ¹ C (O) R ^4a , -OX ¹ NR ^4a R ^4b , -S (O ) X ¹ NR ^4a R ^4b , -S (O) ₂ X ¹ NR ^4a R ^4b , -X ¹ OC (O) NR ^4a R ^4b , -X ¹ NR ^4a C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a C (O) NR ^4a R ^4b , -Y, -X ¹ -Y, -OY, -NR ^4a Y, -SY, -S (O) Y and- Represents a member selected from the group consisting of S (O) ₂ Y. Similarly, R ^{4 ′} is -C (= NH) R ^4a , -C (= NR ^4c ) R ^4a , -C (= NH) NR ^4a R ^4b , -C (= NR ^4c ) NR ^4a R ^4b ,- C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b , -X ² -C (= NH) NR ^4a R ^4b , -X ² -C (= NR ^4c ) NR ^4a R ^4b , -X ² -C ( = N ⁺ R ^4c R ^4c ) NR ^4a R ^4b and -C (= NR ^4a ) NR ^4a represents a member selected from the group consisting of -Y, where Y is halogen, oxo, -OR ^4a , -OC ( O) R ^4a , -NR ^4a R ^4b , -R ^4c , -SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R ^4b , -CN, -NO ₂ , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , -NR ^4b C (O) R ^4a , -NR ^4b C (O) ₂ R ^4c , -X ¹ R ^4a , -X ¹ OR ^4a , -X ¹ SR ^4a , -X ¹ S (O) R ^4a , -X ¹ S (O) ₂ R ^4a , -X ¹ CN, -X ¹ NO ₂ , -X ¹ CO ₂ R ^4a , -X ¹ CONR ^4a R ^4b , -X ¹ C (O) R ^4a , -OX ¹ NR ^4a R ^4b , -S (O) X ¹ NR ^4a R ^4b , -S (O) ₂ X ¹ NR ^4a R ^4b , -X ¹ OC (O) NR ^4a R ^4b , -X ¹ NR ^4b C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a -C (O) NR ^4a R ^4b , -X ¹ OC (O) R ^4a , -X ¹ NR ^4a R ^4b , -OX ¹ OR ^4a , -OX ¹ NR ^4a R ^4b , -OX ¹ CO ₂ R ^4a , -OX ¹ CONR ^4a R ^4b , -N ^{1 to 4} selected from the group consisting of R ^4b -X ¹ OR ^4a , -NR ^4b -X ¹ NR ^4a R ^4b , -NR ^4b -X ¹ CO ₂ R ^4a , and -NR ^4b -X ¹ CONR ^4a R ^4b 5 or 6 membered aryl, heterocyclyl or aryl-C _1-2 alkyl, optionally substituted with 3 substituents; X ¹ and X ² are C _1-4 alkylene, C _2-4 alkenylene, respectively And R ^4a and R ^4b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C ₃ , and C _3-4 alkynylene. Independently selected from the group consisting of _-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl; R each ^4c, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl , C _2-8 alkynyl, aryl, heteroaryl, selected aryl -C _1-4 alkyl, and more independently aryloxy -C _1-4 group consisting of alkyl, and optionally R ^4a, of R ^4b and R ^4c Any two, when part of a common R ⁴ or R ^{4 ′} substituent, combine with the atoms to which each is attached to have 0 to 2 additional heteroatoms as ring members, Saturated or unsaturated, 4-9 membered monocyclic or bicyclic rings can be formed. In addition, R ^4a , R ^4b and R ^4c are each —OH, oxo, —R ^m , —OR ^m , —OC (O) NHR ^m , —OC (O) N (R ^m ) ₂ , —SH, -SR ^m -S (O) R ^m , -S (O) ₂ R ^m , -SO ₂ NH ₂ , -S (O) ₂ NHR ^m , -S (O) ₂ N (R ^m ) ₂ , -NHS (O) ₂ R ^m , -NR ^m S (O) ₂ R ^m , -C (O) NH ₂ , -C (O) NHR ^m , -C (O) N (R ^m ) ₂ , -C (O ) R ^m , -NHC (O) R ^m , -NR ^m C (O) R ^m , -NHC (O) NH ₂ , -NR ^m C (O) NH ₂ , -NR ^m C (O) NHR ^m , -NHC (O) NHR ^m , -NR ^m C (O) N (R ^m ) ₂ , -NHC (O) N (R ^m ) ₂ , -CO ₂ H, -CO ₂ R ^m , -NHCO ₂ R ^m , -NR ^m CO ₂ R ^m , -CN, -NO ₂ , -NH ₂ , -NHR ^m , -N (R ^m ) ₂ , -NR ^m S (O) NH ₂ and -NR ^m S (O) ₂ It may be further substituted with 1 to 3 members selected from the group consisting of NHR ^m , wherein each R ^m is independently unsubstituted C _1-6 alkyl, benzyl, or each bonded. To form a saturated 4, 5, 6 or 7 membered ring with 0 to 2 additional heteroatoms as ring members.

Then with respect to formula (c), the symbols R ⁵ is _{^{-R 5a, -CO 2 R 5c,}} -CONR 5a R 5b, -C (O) R 5a, -C (= NR 5a) NR 5a R 5b, -C (= N ⁺ R ^5c R ^5c ) NR ^5a R ^5b , -C (= NR ^5a ) R ^5a , -C (= NR ^5a ) Y ¹ , -X ³ OR ^5a , -X ³ OC (O) R ^5a , -X ³ NR ^5a R ^5b , -X ³ SR ^5a , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^5a , -X ³ CONR ^5a R ^5b , -X ³ C (O) R ^5a , -X ³ OC (O) NR ^5a R ^5b , -X ³ NR ^5a C (O) R ^5a , -X ³ NR ^5b C (O) ₂ R ^5c , -X ³ NR ^5a C (O) NR ^5a R ^5b represents a member selected from the group consisting of -X ³ -C (= NR ^5a ) NR ^5a R ^5b , -Y ¹ , and -X ³ -Y ¹ , where Y ¹ is halogen, -OR ^5a , -OC (O) R ^5a, -NR ^5a R ^5b , -R ^5c , -SR ^5a , -CN, -NO ₂ , -CO ₂ R ^5a , -CONR ^5a R ^5b , -C (O) R ^5a ,- NR ^5b C (O) R ^5a , -NR ^5b C (O) ₂ R ^5C , -X ³ OR ^5a , -X ³ SR ^5a , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^5a , -X ³ CONR ^5a R ^5b , -X ³ C (O) R ^5a , -X ³ OC (O) NR ^5a R ^5b , -X ³ NR ^5b C (O) R ^5a , -X ³ NR ^5b C ( O) ₂ R ^5c , -X ³ NR ^5a -C (O) NR ^5a R ^5b , -X ³ OC (O) R ^5a , -X ³ NR ^5a R ^5b , -OX ³ OR ^5a ,- OX ³ NR ^5a R ^5b , -OX ³ CO ₂ R ^5a , -OX ³ CONR ^5a R ^5b , -NR ^5b -X ³ OR ^5a , -NR ^5b -X ³ NR ^5a R ^5b , -NR ^5b -X ³ CO 5 or 6-membered aryl or heteroaryl ring or aryl-C optionally substituted with 1 to 3 substituents selected from the group consisting of ₂ R ^5a , and —NR ^5b —X ³ CONR ^5a R ^5b _1-2 alkyl, wherein X ³ is a member independently selected from the group consisting of C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene; R ^5a and R ^5b are each Hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-, respectively Independently selected from the group consisting of C _1-4 alkyl, and aryloxy-C _1-4 alkyl; R ^5c is C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, respectively. Independently from the group consisting of alkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl And optionally any two of R ^5a , R ^5b, and R ^5c , when part of a common R ⁵ substituent, combine with the atom to which each is bonded to 0-1 Saturated 4, 5, 6 or 7 membered rings can be formed having as a ring member any of the following heteroatoms. In addition, R ^5a , R ^5b and R ^5c are -OH, -OR ⁿ , -OC (O) NHR ⁿ , -OC (O) N (R ⁿ ) ₂ , -SH, -SR ⁿ -S ( O) R ⁿ , -S (O) ₂ R ⁿ , -SO ₂ NH ₂ , -S (O) ₂ NHR ⁿ , -S (O) ₂ N (R ⁿ ) ₂ , -NHS (O) ₂ R ⁿ , -NR ⁿ S (O) ₂ R ⁿ , -C (O) NH ₂ , -C (O) NHR ⁿ , -C (O) N (R ⁿ ) ₂ , -C (O) R ⁿ , -NHC (O) R ⁿ , -NR ⁿ C (O) R ⁿ , -NHC (O) NH ₂ , -NR ⁿ C (O) NH ₂ , -NR ⁿ C (O) NHR ⁿ , -NHC (O) NHR ⁿ , -NR ⁿ C (O) N (R ⁿ ) ₂ , -NHC (O) N (R ⁿ ) ₂ , -CO ₂ H, -CO ₂ R ⁿ , -NHCO ₂ R ⁿ , -NR ⁿ CO ₂ From the group consisting of R ⁿ , -CN, -NO ₂ , -NH ₂ , -NHR ⁿ , -N (R ⁿ ) ₂ , -NR ⁿ S (O) NH ₂ and -NR ⁿ S (O) ₂ NHR ⁿ It may be further substituted with 1 to 3 members selected, wherein each R ⁿ is independently unsubstituted C _1-6 alkyl or benzyl.

から選択され、式中、波線は化合物の残部への結合点を示す。より好ましくは、R^4'はイソキサゾールまたはイソキサゾリン環の結合に対してパラの位置でフェニル環に結合している。もう一つの態様群において、下付き文字nは0〜1の整数である。もう一つの態様群において、nは1であり；R⁴はイソキサゾールまたはイソキサゾリン環に対してオルトの位置でフェニル環に結合しており、R^4'はイソキサゾールまたはイソキサゾリン環に対してパラの位置でフェニル環に結合している。一つの態様群において、R⁴はハロゲン、-OR^4a、-NR^4aR^4b、-SR^4a、-Y、-X¹-Y、-O-Y、-NR^4aYおよび-SYからなる群より選択される。 Some specific embodiments of the invention have the above formula. In one group of embodiments,
W has the formula (a). In another embodiment group, the subscript m is 1. In another group of embodiments, R ^{4 ′} can be any of the substituents provided for the full scope of the invention. In one embodiment group, R ^{4 ′} is

Where the wavy line indicates the point of attachment to the remainder of the compound. More preferably, R ^{4 ′} is attached to the phenyl ring at the para position relative to the bond of the isoxazole or isoxazoline ring. In another embodiment group, the subscript n is an integer from 0 to 1. In another group of embodiments, n is 1; R ⁴ is attached to the phenyl ring in the ortho position relative to the isoxazole or isoxazoline ring, and R ^{4 ′} is in the para position relative to the isoxazole or isoxazoline ring. Bonded to the phenyl ring. In one embodiment group, R ⁴ is selected from the group consisting of halogen, -OR ^4a , -NR ^4a R ^4b , -SR ^4a , -Y, -X ¹ -Y, -OY, -NR ^4a Y and -SY. The

からなる群より選択され、式中、波線は化合物の残部への結合点を示す。 In another group of embodiments, m is 0 or 1, n is 0, 1 or 2, and at least one R ⁴ is

Wherein the wavy line indicates the point of attachment to the remainder of the compound.

In another embodiment group, m is 0 or 1; n is 0, 1 or 2; and at least one R ⁴ is -Y, -X ¹ -Y, -OY, -NR ^4a Y,- SY, -S (O) Y and -S (O) ₂ Y are selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl and pyrazolyl, substituted You may be a member. More preferably, R ⁴ is selected from the group consisting of -Y, -X ¹ -Y, -OY and -NR ^4a Y, wherein Y is selected from the group consisting of phenyl, benzyl, pyridyl and pyridylmethyl. A member that may be substituted. More preferably, the optional substituent is halogen, -OR ^4a , -NR ^4a R ^4b , -R ^4c , -SR ^4a , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , It is an embodiment selected from the group consisting of -X ¹ OR ^4a and -X ¹ NR ^4a R ^4b .

In other embodiments, compounds of formula I are provided wherein R ² is present and the carbon attached to R ² has the R configuration. Other embodiments are provided wherein R ³ is other than H and the carbon attached to R ³ has the R configuration.

In another embodiment, there is provided a compound of formula I, wherein W has formula (b). Within this group, certain embodiments are provided wherein Z ¹ is N. Another embodiment is provided wherein Z ² is N. Another embodiment is provided wherein Z ³ is N.

から選択され、式中、波線は化合物の残部への結合点を示す。より好ましくは、R^4'はイソキサゾールまたはイソキサゾリン環の結合に対してパラの位置でピリジル環に結合している。もう一つの態様群において、下付き文字nは0〜1の整数である。もう一つの態様群において、nは1であり；R⁴はイソキサゾールまたはイソキサゾリン環に対してオルトの位置でピリジル環に結合しており、R^4'はイソキサゾールまたはイソキサゾリン環に対してパラの位置でピリジル環に結合している。一つの態様群において、R⁴はハロゲン、-OR^4a、-NR^4aR^4b、-SR^4a、-Y、-X¹-Y、-O-Y、-NR^4aYおよび-SYからなる群より選択される。 In another embodiment group, the subscript m is 1. In another group of embodiments, R ^{4 ′} can be any of the substituents provided for the full scope of the invention. In one embodiment group, R ^{4 ′} is

Where the wavy line indicates the point of attachment to the remainder of the compound. More preferably, R ^{4 ′} is attached to the pyridyl ring at the para position relative to the isoxazole or isoxazoline ring attachment. In another embodiment group, the subscript n is an integer from 0 to 1. In another group of embodiments, n is 1; R ⁴ is attached to the pyridyl ring at the ortho position relative to the isoxazole or isoxazoline ring, and R ^{4 ′} is para to the isoxazole or isoxazoline ring. Bonded to the pyridyl ring. In one embodiment group, R ⁴ is selected from the group consisting of halogen, -OR ^4a , -NR ^4a R ^4b , -SR ^4a , -Y, -X ¹ -Y, -OY, -NR ^4a Y and -SY. The

からなる群より選択され、式中、波線は化合物の残部への結合点を示す。 In another group of embodiments, m is 0 or 1, n is 0, 1 or 2, and at least one R ⁴ is

Wherein the wavy line indicates the point of attachment to the remainder of the compound.

In another group of embodiments, m is 0 or 1; n is 1, 2, or 3; and at least one R ⁴ is —Y, —X ¹ —Y, —OY, —NR ^4a Y, -SY, is selected from the group consisting of -S (O) Y, and -S (O) ₂ Y, wherein Y is phenyl, benzyl, pyridyl, pyridylmethyl, is selected from the group consisting of pyrimidinyl and pyrazolyl, optionally substituted You may be a member. More preferably, R ⁴ is selected from the group consisting of -Y, -X ¹ -Y, -OY and -NR ^4a Y, wherein Y is selected from the group consisting of phenyl, benzyl, pyridyl and pyridylmethyl. A member that may be substituted. More preferably, the optional substituent is halogen, -OR ^4a , -NR ^4a R ^4b , -R ^4c , -SR ^4a , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C (O) R ^4a , It is an embodiment selected from the group consisting of -X ¹ OR ^4a and -X ¹ NR ^4a R ^4b .

In another embodiment, there is provided a compound of formula I, wherein W has formula (c). Other embodiments are provided wherein Y ¹ is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridyl. R ⁵ is selected from the group consisting of -R ^5a , -C (= NH) NR ^5a R ^5b , -C (= NH) R ^5a , -C (= NH) Y ¹ and -X ³ -Y ¹ Other aspects are provided.

In the present invention, the compounds described in the following examples are preferred embodiments together with their pharmaceutically acceptable salts. Preferred examples of compounds of formula (I) include the following:
5-chloro-thiophene-2-carboxylic acid [3- (4-bromo-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (3-bromo-phenyl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-phenoxy-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N-methylcarbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide;
Methyl 5-chloro-thiophene-2-carboxylate- {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide;
1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -methyl-amino] -methyl} -isoxazol-3-yl) -phenyl] -imino-methyl} -piperidine-4- Carboxylic acid ethyl ester;
5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-imino-methyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-azetidin-1-ylidene-methyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N-ethyl-N-methyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide;
Methyl 5-chloro-thiophene-2-carboxylate- {3- [4- (N-methyl-N-propyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-dimethylamino-ethyl) -N-methyl-carbamimidoyl] -phenyl} -isoxazol-5-ylmethyl) -methyl- An amide;
1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -methyl-amino] -methyl} -isoxazol-3-yl) -phenyl] -imino-methyl} -piperidine-4- Carboxylic acid amides;
5-Chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-methoxy-ethyl) -N-methyl-carbamimidoyl] -phenyl} -isoxazol-5-ylmethyl) -methyl-amide ;
5-chloro-thiophene-2-carboxylic acid methyl- {3- [4- (N-methyl-N-prop-2-ynyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
(R) -5-chloro-thiophene-2-carboxylic acid (1- {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide;
(R) -5-Chloro-thiophene-2-carboxylic acid (1- {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide ;
(S) -5-Chloro-thiophene-2-carboxylic acid (1- {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazole-5- Yl} -ethyl) -amide;
(S) -5-chloro-thiophene-2-carboxylic acid (1- {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-pyrrolidin-1-yl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-methylsulfanyl-phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid (3-phenyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid (5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid (3-phenyl-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid (3-p-tolyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid (5-methyl-3-p-tolyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid (3-p-tolyl-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-methoxy-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-methoxy-phenyl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-chloro-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-chloro-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-chloro-phenyl) -isoxazol-5-ylmethyl] -amide;
4- (5-{[(5-chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -benzoic acid methyl ester;
4- (5-{[(5-chloro-thiophen-2-carbonyl) -amino] -methyl} -isoxazol-3-yl) -benzoic acid methyl ester;
4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -benzoic acid;
4- (5-{[(5-chloro-thiophen-2-carbonyl) -amino] -methyl} -isoxazol-3-yl) -benzoic acid;
5-chloro-thiophene-2-carboxylic acid [3- (4-amino-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid (3- {4-[(2-diethylamino-ethyl) -methyl-carbamoyl] -phenyl} -isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid [3- (1-ethyl-piperidin-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (1-benzyl-piperidin-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (1-isopropyl-piperidin-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (1-carbamimidoyl-piperidin-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [1- (1-imino-ethyl) -piperidin-4-yl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [1- (imino-phenyl-methyl) -piperidin-4-yl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [1- (imino-pyridin-2-yl-methyl) -piperidin-4-yl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid (3-piperidin-4-yl-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid [3- (1-ethyl-piperidin-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (1-benzyl-piperidin-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (1-carbamimidoyl-piperidin-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [1- (1-imino-ethyl) -piperidin-4-yl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [1- (imino-phenyl-methyl) -piperidin-4-yl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-formyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-chloro-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-methylsulfanyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-pyridin-4-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-pyridin-3-yl-phenyl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-azepan-1-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-dimethylaminomethyl-5′-methoxy-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-hydroxymethyl-4′-methoxy-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (3′-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4′-dimethylaminomethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4′-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-dimethylaminomethyl-5′-methoxy-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-pyridin-2-yl-phenyl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-benzylamino-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-phenylamino-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (4-fluoro-phenylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-2-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (2-methyl-pyridin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-Chloro-thiophene-2-carboxylic acid (3- {4-[(2-amino-pyrimidin-4-yl) -methyl-amino] -phenyl} -4,5-dihydro-isoxazol-5-ylmethyl)- An amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (2-ethyl-2H-pyrazol-3-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-morpholin-4-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (2-methoxymethyl-pyrrolidin-1-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (5-oxo- [1,4] oxazepan-4-yl) -phenyl] -4,5-dihydro-isoxazol-5- Ilmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-phenylamino-phenyl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (4-methoxy-phenylamino) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-2-ylamino) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (methyl-pyridin-4-yl-amino) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-pyrrolidin-1-yl-phenyl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-morpholin-4-yl-phenyl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-benzylamino-phenyl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-piperidin-4-ylamino) -phenyl] -isoxazol-5-ylmethyl} -amide;
2- [4- (5-{[(5-chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenylamino] -benzoic acid methyl ester;
3- [4- (5-{[(5-chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenylamino] -benzoic acid methyl ester;
4- [4- (5-{[(5-chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenylamino] -benzoic acid methyl ester;
5-chloro-thiophene-2-carboxylic acid [3- (2′-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (3′-dimethylaminomethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (3′-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4′-dimethylaminomethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4′-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-dimethylaminomethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (3′-dimethylaminomethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (3′-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4′-dimethylaminomethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4′-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (3-pyridin-3-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (3-pyridin-4-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; and
5-Chloro-thiophene-2-carboxylic acid [3- (3-pyridin-3-yl-phenyl) -isoxazol-5-ylmethyl] -amide.

Examples of more preferred compounds of formula (I) include:
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenyl] -imino-methyl}- Piperidine-4-carboxylic acid ethyl ester;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-methyl-N-prop-2-ynyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -Amide;
5-Chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-methoxy-ethyl) -N-methyl-carbamimidoyl] -phenyl} -4,5-dihydro-isoxazole-5- Ylmethyl) -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-furan-2-ylmethyl-N-methyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -Amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N-methyl-N-prop-2-ynyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-methoxy-ethyl) -N-methyl-carbamimidoyl] -phenyl} -5-methyl-4,5-dihydro- Isoxazol-5-ylmethyl) -amide;
1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -5-methyl-4,5-dihydro-isoxazol-3-yl) -phenyl] -imino -Methyl} -piperidine-4-carboxylic acid amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-fluoro-phenyl] -dihydro-isoxazol-5-ylmethyl} -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl}- An amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro- Isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl-amide;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-pyrrolidin-1-yl-phenyl] -4,5-dihydro-isoxazole-5- Ilmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-pyrrolidin-1-yl-phenyl] -4,5 -Dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-pyrrolidin-1-yl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-morpholin-4-yl-phenyl] -4,5 -Dihydro-isoxazol-5-ylmethyl} -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-morpholin-4-yl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-morpholin-4-yl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide;
5-Chloro-thiophene-2-carboxylic acid {3- [2-[(2-methoxy-ethyl) -methyl-amino] -4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl ) -Phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid (3- {4- (imino-pyrrolidin-1-yl-methyl) -2-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -4,5 -Dihydro-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid (3- {4- (imino-piperidin-1-yl-methyl) -2-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -4,5 -Dihydro-isoxazol-5-ylmethyl) -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [2-azepan-1-yl-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazole-5- Ilmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (2-methyl-pyrrolidine-1-carbonyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (pyrrolidine-1-carbonyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-amino-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-trifluoromethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-methoxy-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-methoxymethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-pyridin-3-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (5'-chloro-2 '-{[(2-methoxy-ethyl) -methyl-amino] -methyl} -biphenyl-4-yl) -4,5 -Dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (3′-dimethylaminomethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (2-chloro-pyridin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (pyrimidin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-1H-pyrazol-3-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (4-methyl-piperazin-1-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-piperidin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid (3- {4-[(2-dimethylamino-ethyl) -methyl-amino] -phenyl} -4,5-dihydro-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (2-oxo-piperidin-1-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; and
5-Chloro-thiophene-2-carboxylic acid {3- [4- (3-oxo-thiomorpholin-4-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide.

Examples of particularly preferred compounds of formula (I) include the following:
5-chloro-thiophene-2-carboxylic acid [3- (4-cyano-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-Chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-dimethylamino-ethyl) -N-methyl-carbamimidoyl] -phenyl} -4,5-dihydro-isoxazole-5 -Ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N-methyl-N-propyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N-ethyl-N-methyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-cyano-phenyl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -isoxazol-3-yl) -phenyl] -imino-methyl} -piperidine-4-carboxylic acid Ethyl ester;
5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-imino-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-azetidin-1-ylidene-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N-ethyl-N-methyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N-methyl-N-propyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-dimethylamino-ethyl) -N-methyl-carbamimidoyl] -phenyl} -isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N-furan-2-ylmethyl-N-methyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-methoxy-ethyl) -N-methyl-carbamimidoyl] -phenyl} -isoxazol-5-ylmethyl) -amide;
Methyl 5-chloro-thiophene-2-carboxylate- {3- [4- (N-methylcarbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
(R) -5-Chloro-thiophene-2-carboxylic acid (1- {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide ;
(R) -5-Chloro-thiophene-2-carboxylic acid (1- {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazole-5- Yl} -ethyl) -amide;
(R) -5-chloro-thiophene-2-carboxylic acid (1- {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide;
(S) -5-chloro-thiophene-2-carboxylic acid (1- {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl} -amide ;
5-chloro-thiophene-2-carboxylic acid {5-methyl-3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro-isoxazole -5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl} -amide;
1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -5-methyl-4,5-dihydro-isoxazol-3-yl) -phenyl] -imino -Methyl} -piperidine-4-carboxylic acid ethyl ester;
5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-imino-methyl) -phenyl] -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-azetidin-1-ylidene-methyl) -phenyl] -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl } -Amide;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-ethyl-N-methyl-carbamimidoyl) -phenyl] -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl} -Amide;
5-Chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-dimethylamino-ethyl) -N-methyl-carbamimidoyl] -phenyl} -5-methyl-4,5-dihydro -Isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N-furan-2-ylmethyl-N-methyl-carbamimidoyl) -phenyl] -5-methyl-4,5-dihydro-isoxazole- 5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {5-methyl-3- [4- (N-methylcarbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl}- An amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (imino-piperidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide ;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-morpholin-4-yl-phenyl] -4,5-dihydro-isoxazole-5- Ilmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid (3- {4- (N, N-dimethyl-carbamimidoyl) -2-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -4, 5-dihydro-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-azepan-1-yl-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5 -Dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-azepan-1-yl-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-azepan-1-yl-4- (imino-piperidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl-amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -Amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-morpholin-4-yl-phenyl] -isoxazol-5-ylmethyl} -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-morpholin-4-yl-phenyl] -isoxazole-5 -Ilmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-morpholin-4-yl-phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-morpholin-4-yl-phenyl] -isoxazol-5-ylmethyl} -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-methoxy-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide ;
5-chloro-thiophene-2-carboxylic acid {3- [2-methoxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro-isoxazole -5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-methoxy-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-methoxy-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-ethoxy-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide ;
5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro-isoxazole -5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-isopropoxy-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl}- An amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-isopropoxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro- Isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-isopropoxy-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide ;
5-Chloro-thiophene-2-carboxylic acid {3- [2-cyclopentyloxy-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl}- An amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-cyclopentyloxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro- Isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-cyclopentyloxy-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide ;
5-Chloro-thiophene-2-carboxylic acid {3- [2-cyclohexyloxy-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl}- An amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-cyclohexyloxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro- Isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-cyclohexyloxy-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide ;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-methoxy-phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-methoxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl}- An amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-methoxy-phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-methoxy-phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-ethoxy-phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl}- An amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-isopropoxy-phenyl] -isoxazol-5-ylmethyl) -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [2-Isopropoxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -Amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-isopropoxy-phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-isopropoxy-phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-phenoxy-phenyl] -isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-phenoxy-phenyl] -isoxazol-5-ylmethyl}- An amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-phenoxy-phenyl] -isoxazol-5-ylmethyl} -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2- (4-methoxy-phenoxy) -phenyl] -isoxazol-5-ylmethyl} -amide ;
5-Chloro-thiophene-2-carboxylic acid {3- [2- (4-methoxy-phenoxy) -4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazole -5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2- (4-methoxy-phenoxy) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-methylsulfanyl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl}- An amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-methylsulfanyl-phenyl] -4,5-dihydro- Isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-methylsulfanyl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide ;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-methylsulfanyl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide ;
5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-methylsulfanyl-phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-methylsulfanyl-phenyl] -isoxazol-5-ylmethyl} -Amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-methylsulfanyl-phenyl] -isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-amino-phenyl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-dimethylcarbamoyl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidine-1-carbonyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (pyrrolidine-1-carbonyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid (3- {4-[(2-diethylamino-ethyl) -methyl-carbamoyl] -phenyl} -4,5-dihydro-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-pyridin-4-yl-phenyl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-dimethylaminomethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-piperidin-1-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-morpholin-4-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2 '-{[(2-methoxy-ethyl) -methyl-amino] -methyl} -biphenyl-4-yl) -4,5-dihydro-isoxazole- 5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [2 '-(4-methyl-piperazin-1-ylmethyl) -biphenyl-4-yl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide ;
5-Chloro-thiophene-2-carboxylic acid [3- (2 '-{[(2-dimethylamino-ethyl) -methyl-amino] -methyl) -biphenyl-4-yl) -4,5-dihydro-isoxazole -5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (5′-methoxy-2′-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (5′-chloro-2′-dimethylaminomethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (5′-chloro-2′-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2'-formyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2 '-Dimethylaminomethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (5′-methoxy-2′-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (2′-dimethylaminomethyl-4′-methoxy-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4′-methoxy-2′-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid [3- (4-pyridin-2-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-3-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl-amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (methyl-pyridin-4-yl-amino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid (3- {4-[(3-dimethylamino-propyl) -methyl-amino] -phenyl} -4,5-dihydro-isoxazol-5-ylmethyl) -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (2-oxo-pyrrolidin-1-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl) -amide;
4- [4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenyl] -3-oxo-piperazine- 1-carboxylic acid benzyl ester;
5-chloro-thiophene-2-carboxylic acid {3- [4- (3-oxo-morpholin-4-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (3-methyl-2-oxo-imidazolidin-1-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide ;
5-Chloro-thiophene-2-carboxylic acid {3- [4- (5-oxo- [1,4] oxazepan-4-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide ;
5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (pyridin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide;
5-Chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (4-methyl- [1,4] diazepan-1-yl) -phenyl] -4,5-dihydro-isoxazole-5- Ilmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-3-ylamino) -phenyl] -isoxazol-5-ylmethyl} -amide;
5-chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-4-ylamino) -phenyl] -isoxazol-5-ylmethyl} -amide; and
5-Chloro-thiophene-2-carboxylic acid [3- (2′-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide.

5-chloro-N-((3- (4- (2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3- (4- (3-fluoro-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide;
5-chloro-N-((3- (4- (5-fluoro-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene 2-carboxamide;
5-chloro-N-((3- (4- (3-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide;
5-chloro-N-((3- (4- (3-methoxy-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide;
5-chloro-N-((3- (4- (3-chloro-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide;
5-chloro-N-((3- (4- (4-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide;
5-chloro-N-((3- (4- (5-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide;
5-chloro-N-((3- (4- (5-methoxy-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide;
5-chloro-N-((3- (4- (5-chloro-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide;
5-chloro-N-((3- (4-iodophenyl) isoxazol-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3- (4- (2-oxopyridin-1 (2H) -yl) phenyl) isoxazol-5-yl) methyl) thiophene-2-carboxamide;
5-Chloro-N-((1- (4- (2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide ;
5-Chloro-N-((1- (4- (3-fluoro-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-Chloro-N-((1- (4- (3-chloro-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-Chloro-N-((1- (4- (3-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-Chloro-N-((1- (4- (3-methoxy-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-Chloro-N-((1- (4- (4-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-chloro-N-((1- (4- (5-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-Chloro-N-((1- (4- (5-methoxy-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-Chloro-N-((1- (4- (5-fluoro-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-Chloro-N-((1- (4- (5-chloro-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-chloro-N-((1- (4- (2-oxopiperidin-1-yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((1- (4- (3-oxomorpholino) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((1- (4- (3-oxothiomorpholino) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide;
5-Chloro-N-((1- (4- (5-oxo-1,4-oxazepan-4-yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2 -Carboxamide;
5-chloro-N-((1- (2-fluoro-4-iodophenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide;
5-Chloro-N-((1- (2-fluoro-4- (2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-chloro-N-((1- (2-fluoro-4- (3-oxomorpholino) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide;
5-Chloro-N-((1- (2-hydroxy-4- (2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-Chloro-N-((1- (2- (4-methylpiperazin-1-yl) -4- (2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3- Triazol-4-yl) methyl) thiophene-2-carboxamide;
5-Chloro-N-((1- (5- (2-oxopyridin-1 (2H) -yl) pyridin-2-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-chloro-N-((3- (6- (2-oxopyridin-1 (2H) -yl) pyridin-3-yl) isoxazol-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3- (4- (2-oxopyridin-1 (2H) -yl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) thiophene-2-carboxamide;
5-Chloro-N-((1- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl ) Thiophene-2-carboxamide;
N-((1- (4- (N, N-dimethylcarbamimidoyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
N-((1- (4- (N-ethyl-N-methylcarbamimidoyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide ;
N-((1- (4- (N-methyl-N-propylcarbamimidoyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide ;
N-((1- (4- (N- (2-methoxyethyl) -N-methylcarbamimidoyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chloro Thiophene-2-carboxamide;
N-((1- (4- (azetidin-1-yl (imino) methyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((1- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((1- (4- (imino (piperidin-1-yl) methyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide;
N-((1- (4- (N, N-dimethylcarbamimidoyl) -2-fluorophenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2 -Carboxamide;
N-((1- (4- (azetidin-1-yl (imino) methyl) -2-fluorophenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2 -Carboxamide;
5-Chloro-N-((1- (2-fluoro-4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2 -Carboxamide;
5-Chloro-N-((1- (2-fluoro-4- (imino (piperidin-1-yl) methyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2 -Carboxamide;
5-Chloro-N-((1- (2-fluoro-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1H-1,2,3-triazole-4 -Yl) methyl) thiophene-2-carboxamide;
N-((1- (4- (N, N-dimethylcarbamimidoyl) phenyl) -1H-pyrazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-Chloro-N-((1- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1H-pyrazol-4-yl) methyl) thiophene-2-carboxamide ;
N-((1- (4- (azetidin-1-yl (imino) methyl) phenyl) -1H-pyrazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((1- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1H-pyrazol-4-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((1- (4- (imino (piperidin-1-yl) methyl) phenyl) -1H-pyrazol-4-yl) methyl) thiophene-2-carboxamide;
N-((5- (4- (N, N-dimethylcarbamimidoyl) phenyl) isoxazol-3-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((5- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) isoxazol-3-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((5- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) isoxazol-3-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((5- (4- (imino (piperidin-1-yl) methyl) phenyl) isoxazol-3-yl) methyl) thiophene-2-carboxamide;
N-((3- (4- (N, N-dimethylcarbamimidoyl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-Chloro-N-((3- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) thiophene -2-carboxamide;
5-chloro-N-((3- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3- (4- (imino (piperidin-1-yl) methyl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) thiophene-2-carboxamide;
N-((2- (4- (N, N-dimethylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((2- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) oxazol-4-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((2- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) oxazol-4-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((2- (4- (imino (piperidin-1-yl) methyl) phenyl) oxazol-4-yl) methyl) thiophene-2-carboxamide;
1-((4- (4-((2-chlorothiophene-5-carboxamido) methyl) oxazol-2-yl) phenyl) (imino) methyl) piperidine-4-carboxylate;
N-((2- (4- (N-ethyl-N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
N-((2- (4- (N-methyl-N-propylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
N-((2- (4- (N- (2- (dimethylamino) ethyl) -N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
N-((2- (4- (N- (2-methoxyethyl) -N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
1-((4- (4-((2-chlorothiophene-5-carboxamido) methyl) oxazol-2-yl) phenyl) (imino) methyl) piperidine-4-carboxamide;
N-((2- (4- (N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
N-((2- (4- (N- (furan-2-ylmethyl) -N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
N-((2- (4- (N, N-dimethylcarbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((2- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) thiazol-4-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((2- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) thiazol-4-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((2- (4- (imino (piperidin-1-yl) methyl) phenyl) thiazol-4-yl) methyl) thiophene-2-carboxamide;
1-((4- (4-((2-chlorothiophene-5-carboxamido) methyl) thiazol-2-yl) phenyl) (imino) methyl) piperidine-4-carboxylate;
N-((2- (4- (N- (2- (dimethylamino) ethyl) -N-methylcarbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
N-((2- (4- (N- (furan-2-ylmethyl) -N-methylcarbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
N-((2- (4- (N-methyl-N- (prop-2-ynyl) carbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
N-((2- (4- (N-methylcarbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((4- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) oxazol-2-yl) methyl) thiophene-2-carboxamide;
N-((4- (4- (N, N-dimethylcarbamimidoyl) phenyl) thiazol-2-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((4- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) thiazol-2-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((4- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) thiazol-2-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((4- (4- (imino (piperidin-1-yl) methyl) phenyl) thiazol-2-yl) methyl) thiophene-2-carboxamide;
N-((1- (4- (N, N-dimethylcarbamimidoyl) phenyl) -1H-imidazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-Chloro-N-((1- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1H-imidazol-4-yl) methyl) thiophene-2-carboxamide ;
N-((1- (4- (azetidin-1-yl (imino) methyl) phenyl) -1H-imidazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((1- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1H-imidazol-4-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((1- (4- (imino (piperidin-1-yl) methyl) phenyl) -1H-imidazol-4-yl) methyl) thiophene-2-carboxamide;
N-((5- (4- (N, N-dimethylcarbamimidoyl) phenyl) pyridin-3-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((5- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) pyridin-3-yl) methyl) thiophene-2-carboxamide;
N-((5- (4- (azetidin-1-yl (imino) methyl) phenyl) pyridin-3-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((5- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) pyridin-3-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((5- (4- (imino (piperidin-1-yl) methyl) phenyl) pyridin-3-yl) methyl) thiophene-2-carboxamide;
N-((5- (4- (N, N-dimethylcarbamimidoyl) phenyl) -2-fluorophenyl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((5- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -2-fluorophenyl) methyl) thiophene-2-carboxamide;
5-chloro-N-((5- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -2-fluorophenyl) methyl) thiophene-2-carboxamide;
N-((3- (4- (N, N-dimethylcarbamimidoyl) phenyl) -4-fluorophenyl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((3- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -4-fluorophenyl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -4-fluorophenyl) methyl) thiophene-2-carboxamide;
N-((3- (4- (N, N-dimethylcarbamimidoyl) phenyl) phenyl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((3- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) phenyl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) phenyl) methyl) thiophene-2-carboxamide;
5-Chloro-N-((1- (6- (4-methyl-1,4-diazepan-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl ) Thiophene-2-carboxamide;
N-((1- (6- (1,4-diazepan-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2 -Carboxamide;
N-((1- (6- (1,4-Oxazepan-4-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2 -Carboxamide;
5-chloro-N-((1- (6-morpholinopyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((1- (6- (3-oxomorpholino) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide;
5-Chloro-N-((1- (6- (2-oxopiperidin-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophen-2- Carboxamide;
5-Chloro-N-((1- (6- (2-oxopyridin-1 (2H) -yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide;
5-chloro-N-((1- (6- (piperazin-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide;
5-Chloro-N-((1- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophen-2- Carboxamide;
5-chloro-N-((1- (6- (piperidin-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3- (4- (8- (trifluoromethyl) quinolin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide ;
5-chloro-N-((3- (4- (7- (trifluoromethyl) quinolin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide ;
5-chloro-N-((3- (4- (6- (trifluoromethyl) quinolin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide ;
5-chloro-N-((3- (4- (quinolin-6-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3- (4- (2,5-dihydro-1H-pyrrol-1-carbonyl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2- Carboxamide;
5-chloro-N-((3- (4- (2,5-dihydro-1H-pyrrol-1-carbonyl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2- Carboxamide;
N-((3- (4-((2-hydroxypropyl) carbamoyl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) -5-chlorothiophene-2-carboxamide;
5-chloro-N-((3- (4- (3-methylpyridin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3- (4- (2-ethoxypyridin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3- (4- (3,5-dichloropyridin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; and
5-chloro-N-((3- (4- (3- (trifluoromethyl) pyridin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide .

  The aforementioned preferred, more preferred and most preferred compounds are all selective inhibitors of factor Xa.

Compositions The present invention further provides compositions comprising one or more compounds of formula (I), or tautomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. It will be appreciated that the compounds of formula (I) in the present invention may be derivatized with functional groups to provide prodrug derivatives that can be converted in vivo to the parent compound. Examples of such prodrugs are physiologically acceptable, such as methoxymethyl ester, methylthiomethyl ester, or pivaloyloxymethyl ester, derived from a carbamoyl moiety derived from the hydroxyl group of the compound or the amino group of the compound, And metabolically unstable ester derivatives. In addition, any physiologically acceptable equivalent of a compound of formula (I), similar to a metabolically labile ester or carbamate, capable of generating the parent compound of formula (I) in vivo It is within the scope of the present invention.

  When pharmaceutically acceptable salts of the compounds of the present invention are used in these compositions, such salts are preferably derived from inorganic or organic acids or bases. Such acid salts include: acetate, adipate, alginic acid, aspartate, benzoate, benzenesulfonate, hydrogen sulfate, butyrate, citrate, camphorate , Camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloric acid Salt, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamo Acid salt, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanic acid Salts, toluenesulfonate and undecanoate. Basic salts include alkali metal salts such as ammonium salts, sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, And salts with amino acids such as arginine and lysine.

  In addition, basic nitrogen-containing groups include lower alkyl halides such as methyl chloride, bromide and iodide, ethyl, propyl and butyl; dialkyl sulfates such as dimethyl sulfate, diethyl, dibutyl and diamyl sulfate, chloride, bromide and iodide. It may be quaternized with substances such as long chain halides such as decyl, lauryl, myristyl and stearyl; aralkyl halides such as benzyl bromide and phenethyl bromide. Water or oil-soluble or dispersible products are thereby obtained.

  The compounds used in the compositions and methods of the present invention can also be modified by adding appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system, etc.), increase oral availability, and allow administration by injection. To increase solubility, alter metabolism, and change excretion rates.

  The pharmaceutical compositions of the present invention can be manufactured by methods well known in the art, such as in particular conventional granulation, mixing, dissolution, encapsulation, lyophilization, or emulsification processes. Compositions are granules, precipitates or microparticles; powders including lyophilized, rotary dried or spray dried powders; amorphous powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions Or you may prepare in various dosage forms containing a liquid agent. The formulation may optionally include stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations thereof.

  Pharmaceutical formulations may be prepared as suspensions or solutions using sterile liquids such as oil, water, alcohol, and combinations thereof. For oral or parenteral administration, pharmaceutically suitable surfactants, suspending agents or emulsifiers may be added. Suspensions may include oils such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparations may contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may also include alcohols such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers such as poly (ethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water can also be used in suspension formulations.

  Pharmaceutically acceptable carriers that can be used in these compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbine Acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, Polyvinylpyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycols and wool oils.

  According to a preferred embodiment, the composition of the invention is formulated for pharmaceutical administration to a mammal, preferably a human. Such pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. As used herein, the term “parenteral” refers to subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intramaternal, intrathecal, intrahepatic, intralesional, and intracranial injection or Includes injection method. Preferably the composition is injected orally or intravenously. The formulations of the present invention may be designed as short acting, immediate release, or long acting. In addition, the compounds can be administered in a local rather than systemic manner, such as administration as a sustained release formulation (eg, injection).

  Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid and their glyceride derivatives, especially their polyoxyethyl forms, are useful in the preparation of injectables, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions are long chain alcohol diluents such as carboxymethylcellulose or similar dispersants commonly used in pharmaceutically acceptable dosage form formulations, including emulsions and suspensions. A dispersant may be included. Other commonly used surfactants such as Tween, Span and other emulsifiers or bioavailability promoters commonly used in the production of pharmaceutically acceptable solid, liquid, or other dosage forms Can be used for pharmaceutical purposes. The compounds can also be formulated for parenteral administration by injection, such as a bolus injection or continuous infusion. Unit dosage forms for injection may be in ampoules or in multi-dose containers.

  The pharmaceutical composition of the present invention may be in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. A lubricant such as magnesium stearate is also typically added. For capsule dosage forms, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may be added.

  Alternatively, the pharmaceutical composition of the present invention may be in the form of a suppository for rectal administration. These should be prepared by mixing the drug with a suitable nonirritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Can do. Such materials include cocoa butter, beeswax, and polyethylene glycol.

  The pharmaceutical compositions of the present invention may be in topical dosage forms, particularly where the therapeutic target is a site or tissue that is easily accessible by topical application, including the eye, skin, or lower gastrointestinal tract. . Appropriate topical formulations are readily prepared for each of these sites or organs.

  Topical application for the lower gastrointestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches can also be used. For topical application, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of this invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. . Alternatively, the pharmaceutical composition may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester, wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

  For use in the eye, the pharmaceutical composition may be stored as a particulate suspension in pH-adjusted isotonic sterile saline, or preferably as a solution in pH-adjusted isotonic sterile saline, such as benzylalkonium chloride. It may be formulated with an agent or without a preservative. Alternatively, the pharmaceutical composition can be formulated in an ointment such as petrolatum for use in the eye.

  The pharmaceutical compositions of the invention may be administered by nasal aerosol or inhalation. Such compositions are prepared by techniques known in the pharmaceutical formulation arts and include benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorinated hydrocarbons and / or other conventional May be prepared as a solution in saline.

Any of the foregoing dosage forms containing an effective amount are within the scope of routine experimentation and are within the scope of the invention. A therapeutically effective dose may vary depending on the route of administration and dosage form. Preferred compounds or compositions of the invention are formulations that exhibit a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects and can be expressed as the ratio between LD ₅₀ and ED ₅₀ . LD ₅₀ is a lethal dose to 50% of the population and ED ₅₀ is a therapeutically effective dose in 50% of the population. LD ₅₀ and ED ₅₀ are determined by standard pharmaceutical methods in animal cell cultures or experimental animals.

  In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers and dosage forms are generally known to those skilled in the art and are included in the invention. The specific dose and treatment for any particular patient will depend on the activity of the particular compound used, the patient's age, weight, general health, gender and diet, and time of administration, elimination rate, concomitant drugs, the treating physician It should be understood that it depends on a variety of factors, including the determination of and the severity of the particular disease being treated. The amount of active ingredient also depends on the particular compound in the composition and other therapeutic agents, if any.

Methods of Use Inhibiting or reducing factor Xa activity, as well as treating or ameliorating a factor Xa related condition, symptom, disorder or disease in a patient in need thereof (eg, a human or non-human) Provide a method. “Treatment” in the context of the present invention means the alleviation of symptoms associated with a disorder or disease, or the cessation of further progression or worsening of those symptoms, or the prevention or prevention of a disease or disorder.

  The term “mammal” includes organisms that express factor Xa. Examples of mammals include mice, rats, cows, sheep, pigs, goats, horses, bears, monkeys, dogs, cats, and preferably humans. Included in this definition are transformed organisms that express factor Xa.

  The methods of the invention comprise administering an effective amount of a compound or composition described herein to a mammal or non-human animal. As used herein, an “effective amount” of a compound or composition of the invention includes an amount that antagonizes or inhibits factor Xa. An amount that antagonizes or inhibits factor Xa can be detected by any assay that can assess factor Xa activity, including, for example, those described below as exemplary test methods. An effective amount can also include an amount that reduces the symptoms of a Factor Xa related disorder treatable by inhibiting Factor Xa. Accordingly, a “factor Xa antagonist” modulates, eg, inhibits or reduces, the ability of a second compound, eg, another factor Xa ligand, to interact with factor Xa and interact with factor Xa. Containing compounds. The factor Xa binding compound is preferably an antagonist of factor Xa. The term “Factor Xa binding compound” (eg, exhibiting binding affinity to the receptor) includes compounds that interact with Factor Xa and thereby modulate the activity of Factor Xa. Factor Xa binding compounds can be identified using in vitro (eg, by cells and non-cells) or in vivo methods. A description of the in vitro method is given below.

  The amount of compound in the methods and compositions described herein should be sufficient to cause a detectable reduction in the severity of the disorder as measured by any of the assays described in the Examples. is there. The amount of factor Xa modulator required will depend on the effectiveness of the modulator for a given cell type and the time period required to treat the disorder. In certain embodiments, the compositions of the present invention may further comprise another therapeutic agent. When a second agent is used, the second agent can be administered as a separate dosage form or as part of a single dosage form with a compound or composition of the invention. In the application of monotherapy to treat a disorder, disease or condition, one or more of the compounds of the invention can be used, but these may be used in combination therapy, in which case The use of a compound or composition (therapeutic agent) is combined with the use of one or more other therapeutic agents to treat the same and / or other types of disorders, symptoms and diseases. Combination therapy includes simultaneous or sequential administration of multiple therapeutic agents. The drugs may be administered in any order. Alternatively, multiple therapeutic agents can be combined into a single composition that can be administered to a patient. For example, one pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt or solvate, another therapeutic agent (e.g. methotrexate) or a pharmaceutically acceptable salt or solvate thereof, And a pharmaceutically acceptable excipient or carrier.

  The present invention relates to a compound having formula I, a process for preparing a compound of the present invention, a process for preparing a pharmaceutical composition from at least one compound of the present invention and at least one pharmaceutically acceptable carrier or excipient, And various disorders, symptoms and diseases such as RA, osteoarthritis, irritable bowel disease IBD, asthma, chronic obstructive pulmonary disease COPD and MS (e.g. inflammatory, autoimmune, neurogenic, neurodegenerative, tumors Including the use of one or more compounds of the invention to treat (sex and cardiovascular). The compounds of the present invention and their pharmaceutically acceptable salts and / or neutral compositions may be formulated with pharmaceutically acceptable excipients or carriers, and the resulting compositions may have various disorders, symptoms. And to treat diseases, it may be administered in vivo to mammals such as men, women and animals. Furthermore, the compounds of the invention can be used to prepare drugs that are useful for treating various disorders, symptoms and diseases.

Kits Yet another aspect of the present invention is a kit comprising separate containers in a package, wherein the pharmaceutical of the present invention is used to treat conditions, disorders, symptoms and diseases in which factor Xa plays a role. It is to provide a kit in which a chemical compound, composition and / or salt thereof is used in combination with a pharmaceutically acceptable carrier.

Example Example 1
5-Chloro-thiophene-2-carboxylic acid [3- (4-bromo-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide (7)
Scheme 1

Stage 1:
Aldehyde 1 was dissolved in 200 mL of ethanol and then treated with pyridine (24 mL, 297 mmol) and hydroxylamine hydrochloride (19.58 g, 284 mmol) to give a clear colorless solution that was stirred overnight. The next day, the reaction was confirmed to be complete by HPLC and TLC, diluted with water (1 L) and filtered to give 2 as a white solid (69 g, quantitative), which contained a small amount of ethanol.

Stage 2:
The undried product from the previous step (270 mmol, theoretical) was dissolved in DMF (140 mL) and treated with N-chlorosuccinimide (38 g, 284 mmol) to give a yellow suspension, which was Stir overnight. The next day, the reaction mixture was diluted with water (1 L), filtered and then suction dried to give the desired product 3 as a slightly yellow solid (75.6 g, quantitative), which contains a small amount of DMF. It was out.

Stage 3:
Carboxylic acid 4 (40 g, 246 mmol) was dissolved in dichloromethane (200 mL) and then treated with oxalyl chloride (32 mL, 368 mmol) and 15 drops of DMF. The reaction mixture generated a constant flow of gas and was stirred at room temperature overnight. The next day, all solids dissolved and the reaction mixture was light brown. A small amount was removed, diluted with methanol and a small amount of triethylamine, concentrated and examined by NMR, which showed only the methyl ester. Concentrate to a brown oil, then stopper the flask and seal with Teflon tape. The yield was not calculated. Methyl ester:

Stage 4:
Allylamine (56.8 mL, 91 mmol) is dissolved in 100 mL dichloromethane, cooled to 0 ° C. and then treated with triethylamine (21 mL, 155 mmol), followed by the slow addition of acid chloride 5 (15 g, 83 mmol) in a small amount of dichloroethane. It was. After confirming the completion of addition by TLC, it was partitioned with NaHCO ₃ aqueous solution, separated, and the organic layer was extracted again with dichloromethane. The combined organic layers were dried over Na ₂ SO _4, concentrated, and purified by filtration through a short silica gel plug to give the desired product (6) in a bright beige crystalline solid (24 g, quantitative ).

Stage 5:
Alkene 6 (4.00 g, 20 mmol) and triethylamine (3.62 mL, 26 mmol) were heated to 90 ° C. until all solids dissolved. The mixture was then treated slowly with 3 (5.14 g, 22 mmol) over 5 minutes. After all 3 was added, the reaction was checked by TLC and if there was a starting alkene, 3 was further added. After 6 was completely consumed, the reaction mixture was cooled to room temperature, concentrated in vacuo, then suspended in a small amount of methanol (ca. 5 mL) and triturated with water to give a white solid. The solid was filtered and dried to give the desired isoxazolidinone (7) as a white solid (6.02 g, 75%).

標題化合物を、実施例1に記載のものと同様の方法により、アリルアミンの代わりにプロパルギルアミンを用いて調製した。

Example 2
5-Chloro-thiophene-2-carboxylic acid [3- (4-bromo-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 1 using propargylamine instead of allylamine.

標題化合物を、実施例1に記載のものと同様の方法により調製した。

Example 3
5-Chloro-thiophene-2-carboxylic acid [3- (3-bromo-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 1.

標題化合物を、実施例2に記載のものと同様の方法により調製した。

Example 4
5-Chloro-thiophene-2-carboxylic acid [3- (3-bromo-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 2.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₂₁H₁₇ClN₂O₃Sについて(M+H)⁺としての実測値：413.5。 Example 5
5-Chloro-thiophene-2-carboxylic acid [3- (4-phenoxy-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 1. _{MS: C 21 H 17 ClN 2} O 3 for S (M ⁺ H) + as the measured value: 413.5.

標題化合物を、実施例2に記載のものと同様の方法により調製した。MS：C₂₁H₁₅ClN₂O₃Sについて(M+H)⁺としての実測値：411.4、413.4。 Example 6
5-Chloro-thiophene-2-carboxylic acid [3- (4-phenoxy-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 2. _{MS: C 21 H 15 ClN 2} O 3 for S (M ⁺ H) + as the measured value: 411.4,413.4.

標題化合物を、実施例1に記載のものと同様の方法により調製した。

Example 7
5-Chloro-thiophene-2-carboxylic acid [3- (4-cyano-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 1.

実施例7からのニトリル(1.00g、2.9mmol)およびトリエチルアミン(1.62mL、11.6mmol)を30mLの1,4-ジオキサンと混合し、H₂S雰囲気下に終夜置いた。次の日、粗製混合物を減圧下で蒸発させ、次いで30mLのアセトンおよびヨウ化メチル(1.44mL、23.2mmol)で希釈し、次いですべての出発原料であるチオアミドがイミデートに変換されるまで(2時間)還流した。次いで、反応混合物を冷却し、ロータリーエバポレーションで濃縮して、粘稠橙色泡状物を得た。橙色泡状物を30mLのTHFに溶解し、7.5mLの一定量を取り出して、ジメチルアミン(0.5M)および酢酸(7.5M)を含むTHF溶液7.5mLで処理した。得られた淡黄色混合物を室温で終夜撹拌したところ、きれいにアミジンに変換された。反応混合物を濃縮し、prep-HPLCで精製して、標題化合物をTFAを含む白色粉末で得た。MS：C₁₈H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：391.0、393.0。 Example 8
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

Nitrile from Example 7 (1.00 g, 2.9 mmol) and triethylamine (1.62 mL, 11.6 mmol) were mixed with 30 mL of 1,4-dioxane and placed under an H ₂ S atmosphere overnight. The next day, the crude mixture was evaporated under reduced pressure, then diluted with 30 mL acetone and methyl iodide (1.44 mL, 23.2 mmol), then until all starting thioamide was converted to imidate (2 h ) Reflux. The reaction mixture was then cooled and concentrated by rotary evaporation to give a viscous orange foam. The orange foam was dissolved in 30 mL of THF and a 7.5 mL aliquot was removed and treated with 7.5 mL of a THF solution containing dimethylamine (0.5 M) and acetic acid (7.5 M). The resulting pale yellow mixture was stirred overnight at room temperature and converted neatly into amidine. The reaction mixture was concentrated and purified by prep-HPLC to give the title compound as a white powder containing TFA. _{MS: C 18 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 391.0,393.0.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₁₉H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：403.1、405.1。 Example 9
5-Chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 19 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 403.1,405.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₀H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：417.1、419.1。 Example 10
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 20 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 417.1,419.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₁H₂₃ClN₄O₂Sについて(M+H)⁺としての実測値：431.1、433.1。 Example 11
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 21 H 23 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 431.1,433.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₄H₂₇ClN₄O₄Sについて(M+H)⁺としての実測値：503.1、505.1。 Example 12
1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenyl] -imino-methyl}- Piperidine-4-carboxylic acid ethyl ester

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 24 H 27 ClN 4} O 4 for S (M ⁺ H) + as the measured value: 503.1,505.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：415.1、417.1。 Example 13
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-methyl-N-prop-2-ynyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -Amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 20 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 415.1,417.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₀H₂₃ClN₄O₃Sについて(M+H)⁺としての実測値：435.1、437.1。 Example 14
5-Chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-methoxy-ethyl) -N-methyl-carbamimidoyl] -phenyl} -4,5-dihydro-isoxazole-5- (Ilmethyl) -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 20 H 23 ClN 4} O 3 for S (M ⁺ H) + as the measured value: 435.1,437.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₂H₂₁ClN₄O₃Sについて(M+H)⁺としての実測値：457.1、459.1。 Example 15
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-furan-2-ylmethyl-N-methyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -Amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 22 H 21 ClN 4} O 3 for S (M ⁺ H) + as the measured value: 457.1,459.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₁H₂₆ClN₅O₂Sについて(M+H)⁺としての実測値：448.1、450.1。 Example 16
5-Chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-dimethylamino-ethyl) -N-methyl-carbamimidoyl] -phenyl} -4,5-dihydro-isoxazole-5 -Ilmethyl) -amide

The title compound was prepared in a similar manner as described in Example 8. MS: C ₂₁ H ₂₆ ClN about _{5 O 2 S (M + H} ) + as the measured value: 448.1,450.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₀H₂₃ClN₄O₂Sについて(M+H)⁺としての実測値：419.1、421.1。 Example 17
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-methyl-N-propyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 20 H 23 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 419.1,421.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₁₉H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：405.1、407.1。 Example 18
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-ethyl-N-methyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 19 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 405.1,407.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₁₉H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：403.1、405.1。 Example 19
5-Chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-imino-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 19 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 403.1,405.1.

標題化合物を、実施例2に記載のものと同様の方法により調製した。

Example 20
5-Chloro-thiophene-2-carboxylic acid [3- (4-cyano-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 2.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₁₈H₁₇ClN₄O₂Sについて(M+H)⁺としての実測値：389.1、391.1。 Example 21
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. _{MS: C 18 H 17 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 389.1,391.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₁₉H₁₇ClN₄O₂Sについて(M+H)⁺としての実測値：401.1、403.1。 Example 22
5-Chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. _{MS: C 19 H 17 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 401.1,403.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₂₀H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：415.1、417.1。 Example 23
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. _{MS: C 20 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 415.1,417.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₂₁H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：429.1、431.1。 Example 24
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. _{MS: C 21 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 429.1,431.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₂₄H₂₅ClN₄O₄Sについて(M+H)⁺としての実測値：501.0、503.1。 Example 25
1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -isoxazol-3-yl) -phenyl] -imino-methyl} -piperidine-4-carboxylic acid Ethyl ester

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. _{MS: C 24 H 25 ClN 4} O 4 for S (M ⁺ H) + as the measured value: 501.0,503.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₁₉H₁₇ClN₄O₂Sについて(M+H)⁺としての実測値：401.1、403.1。 Example 26
5-Chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-imino-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. _{MS: C 19 H 17 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 401.1,403.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₂₂H₂₂ClN₄O₂Sについて(M)⁺としての実測値：441.1、443.1。 Example 27
5-Chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-azetidin-1-ylidene-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. MS: C ₂₂ H ₂₂ ClN about ₄ O ₂ S (M) ⁺ As measured value: 441.1,443.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₁₉H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：403.1、405.1。 Example 28
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-ethyl-N-methyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. _{MS: C 19 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 403.1,405.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₂₀H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：417.1、419.1。 Example 29
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-methyl-N-propyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl-amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. _{MS: C 20 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 417.1,419.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₂₁H₂₄ClN₅O₂Sについて(M+H)+としての実測値：446.1、448.1。 Example 30
5-Chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-dimethylamino-ethyl) -N-methyl-carbamimidoyl] -phenyl} -isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. MS: C ₂₁ H ₂₄ ClN about _{5 O 2 S (M + H} ) + as the measured value: 446.1,448.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₂₂H₁₉ClN₄O₃Sについて(M+H)+としての実測値：455.1、457.1。 Example 31
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-furan-2-ylmethyl-N-methyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. _{MS: C 22 H 19 ClN 4} O 3 for S (M + H) + as the measured value: 455.1,457.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₂₀H₂₁ClN₄O₃Sについて(M+H)+としての実測値：433.1、435.1。 Example 32
5-Chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-methoxy-ethyl) -N-methyl-carbamimidoyl] -phenyl} -isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. _{MS: C 20 H 21 ClN 4} O 3 for S (M + H) + as the measured value: 433.1,435.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₂₀H₁₇ClN₄O₂Sについて(M+H)+としての実測値：413.1、415.1。 Example 33
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-methyl-N-prop-2-ynyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. _{MS: C 20 H 17 ClN 4} O 2 for S (M + H) + as the measured value: 413.1,415.1.

標題化合物を、実施例8に記載のものと同様の方法により、実施例20〜のニトリルを用いて調製した。MS：C₁₇H₁₅ClN₄O₂Sについて(M+H)+としての実測値：375.1、377.1。 Example 34
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-methylcarbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8 using the nitriles of Examples 20-. _{MS: C 17 H 15 ClN 4} O 2 for S (M + H) + as the measured value: 375.1,377.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₁₉H₁₉ClN₄O₂Sについて(M+H)+としての実測値：403.1、405.1。 Example 35
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 19 H 19 ClN 4} O 2 for S (M + H) + as the measured value: 403.1,405.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClN₄O₂Sについて(M+H)+としての実測値：415.1、417.1。 Example 36
5-Chloro-thiophene-2-carboxylic acid methyl- {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 20 H 19 ClN 4} O 2 for S (M + H) + as the measured value: 415.1,417.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₁H₂₁ClN₄O₂Sについて(M+H)+としての実測値：429.1、431.1。 Example 37
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 21 H 21 ClN 4} O 2 for S (M + H) + as the measured value: 429.1,431.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₂H₂₃ClN₄O₂Sについて(M+H)+としての実測値：443.1、445.1。 Example 38
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 22 H 23 ClN 4} O 2 for S (M + H) + as the measured value: 443.1,445.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₅H₂₇ClN₄O₄Sについて(M+H)+としての実測値：515.1、517.1。 Example 39
1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -methyl-amino] -methyl} -isoxazol-3-yl) -phenyl] -imino-methyl} -piperidine-4- Carboxylic acid ethyl ester

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 25 H 27 ClN 4} O 4 for S (M + H) + as the measured value: 515.1,517.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClN₄O₂Sについて(M+H)+としての実測値：415.1、417.0。 Example 40
5-Chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-imino-methyl) -phenyl] -isoxazol-5-ylmethyl] -methyl-amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 20 H 19 ClN 4} O 2 for S (M + H) + as the measured value: 415.1,417.0.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₃H₂₄ClN₄O₂Sについて(M)+としての実測値：455.1、457.1。 Example 41
5-Chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-azetidin-1-ylidene-methyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 23 H 24 ClN 4} O 2 for S (M) + As measured value: 455.1,457.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₀H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：417.1、419.1。 Example 42
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-ethyl-N-methyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl) -methyl-amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 20 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 417.1,419.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₁H₂₃ClN₄O₂Sについて(M+H)⁺としての実測値：431.1、433.1。 Example 43
5-Chloro-thiophene-2-carboxylic acid methyl- {3- [4- (N-methyl-N-propyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 21 H 23 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 431.1,433.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₂H₂₆ClN₅O₂Sについて(M+H)⁺としての実測値：460.1、462.1。 Example 44
5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-dimethylamino-ethyl) -N-methyl-carbamimidoyl] -phenyl} -isoxazol-5-ylmethyl) -methyl- Amide

The title compound was prepared in a similar manner as described in Example 8. MS: C ₂₂ H ₂₆ ClN about _{5 O 2 S (M + H} ) + as the measured value: 460.1,462.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₃H₂₄ClN₅O₃Sについて(M+H)⁺としての実測値：486.1、488.1。 Example 45
1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -methyl-amino] -methyl} -isoxazol-3-yl) -phenyl] -imino-methyl} -piperidine-4- Carboxylic acid amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 23 H 24 ClN 5} O 3 for S (M ⁺ H) + as the measured value: 486.1,488.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₁H₂₃ClN₄O₃Sについて(M+H)⁺としての実測値：447.1、449.1。 Example 46
5-Chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-methoxy-ethyl) -N-methyl-carbamimidoyl] -phenyl} -isoxazol-5-ylmethyl) -methyl-amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 21 H 23 ClN 4} O 3 for S (M ⁺ H) + as the measured value: 447.1,449.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₁H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：427.0、429.1。 Example 47
5-Chloro-thiophene-2-carboxylic acid methyl- {3- [4- (N-methyl-N-prop-2-ynyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 21 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 427.0,429.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₁₈H₁₇ClN₄O₂Sについて(M+H)⁺としての実測値：389.1、391.1。 Example 48
5-Chloro-thiophene-2-carboxylic acid methyl- {3- [4- (N-methylcarbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 18 H 17 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 389.1,391.1.

Scheme 2

段階1：
メチルエステル8(4.03g、19.9mmol)を40mLのトルエンで希釈し、-78℃まで冷却した。トルエン中の水素化ジイソブチルアルミニウム(26mL、40mmol)をあらかじめ冷却した混合物にフラスコの側壁にそってゆっくり加えた。反応混合物を-78℃で2時間撹拌し、その時点であらかじめ冷却したメタノール約5mLでゆっくり処理した(激しい反応)。次いで、混合物を室温まで加温し、飽和酒石酸カリウムナトリウムおよび酢酸エチルで分配した。層を分離し、有機相を酢酸エチルで抽出し、合わせた有機層をMgSO₄で乾燥した。ろ過し、減圧濃縮した後、粗製材料を短いシリカゲルプラグを通してろ過し、ジクロロメタンで溶出することにより精製して、アルデヒド9を無色油状物で得た(2.23g、65％)。

Example 49
(R) -5-Chloro-thiophene-2-carboxylic acid (1- {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide

Stage 1:
Methyl ester 8 (4.03 g, 19.9 mmol) was diluted with 40 mL toluene and cooled to -78 ° C. Diisobutylaluminum hydride in toluene (26 mL, 40 mmol) was slowly added to the precooled mixture along the side wall of the flask. The reaction mixture was stirred at −78 ° C. for 2 hours, at which time it was slowly treated with about 5 mL of precooled methanol (violent reaction). The mixture was then warmed to room temperature and partitioned with saturated potassium sodium tartrate and ethyl acetate. The layers were separated, the organic phase was extracted with ethyl acetate and the combined organic layers were dried over MgSO ₄ . After filtration and concentration in vacuo, the crude material was purified by filtration through a short silica gel plug and eluting with dichloromethane to give aldehyde 9 as a colorless oil (2.23 g, 65%).

Stage 2:
Triphenylphosphine (6.0 g, 23.1 mmol) was dissolved in 30 mL dichloromethane and cooled to 0 ° C. To this was slowly added CBr ₄ (3.84 g, 11.6 mmol) to give a clear orange solution. After stirring for 10 minutes, aldehyde 9 (1.og, 5.78 mmol) was added slowly to give a dark red turbid solution. This was then checked by TLC and found complete consumption of starting material and less polar spots. The reaction mixture was concentrated in vacuo and then filtered through a short silica gel pad (eluting with dichloromethane) to give the desired olefin 10 as an off-white crystalline solid (1.25 g, 66%). %).

Stage 3:
Dibromoolefin 10 (1.25 g, 3.8 mmol) is dissolved in THF (10 mL), cooled to 0 ° C. and then treated with freshly prepared lithium diisopropylamide (1.7 M, 20 mL), during which time the reaction mixture becomes colorless to dark. It turned yellow-orange. The ice bath was removed and the reaction mixture was stirred for 10 minutes. The reaction mixture was then partitioned with 1M HCl and ethyl acetate, the layers were separated, and the aqueous phase was extracted again with ethyl acetate. The combined organic layers were dried over MgSO ₄ , filtered, concentrated and purified by silica gel chromatography (dichloromethane) to give the desired alkyne (11) as a white solid (0.3652 g, 57%).

Stage 4:
Performed in the same manner as Example 1, Step 5.

Stage 5:
Boc protected amine 12 was diluted with 4M HCl / dioxane (10 mL) and stirred for 2 h, at which point TLC was confirmed complete. The reaction mixture was concentrated to give the desired amine as a white solid that was used immediately for the next step.

Stage 6:
Performed in the same manner as Example 1, Step 5.

Stage 7:
Performed in the same manner as Example 8. _{MS: C 19 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 403.1,405.1.

標題化合物を、実施例49に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：415.1、417.1。 Example 50
(R) -5-Chloro-thiophene-2-carboxylic acid (1- {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazole-5- Yl} -ethyl) -amide

The title compound was prepared in a similar manner as described in Example 49. _{MS: C 20 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 415.1,417.1.

標題化合物を、実施例49に記載のものと同様の方法により調製した。MS：C₂₁H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：429.1、430.0。 Example 51
(R) -5-Chloro-thiophene-2-carboxylic acid (1- {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide

The title compound was prepared in a similar manner as described in Example 49. _{MS: C 21 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 429.1,430.0.

標題化合物を、実施例49に記載のものと同様の方法により調製した。MS：C₂₂H₂₃ClN₄O₂Sについて(M+H)⁺としての実測値：443.1、445.1。 Example 52
(R) -5-Chloro-thiophene-2-carboxylic acid (1- {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide

The title compound was prepared in a similar manner as described in Example 49. _{MS: C 22 H 23 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 443.1,445.1.

標題化合物を、実施例49に記載のものと同様の方法により調製した。MS：C₁₉H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：403.0、405.0。 Example 53
(R) -5-Chloro-thiophene-2-carboxylic acid (1- {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide

The title compound was prepared in a similar manner as described in Example 49. _{MS: C 19 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 403.0,405.0.

標題化合物を、実施例49に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：415.0、417.0。 Example 54
(S) -5-Chloro-thiophene-2-carboxylic acid (1- {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazole-5- Yl} -ethyl) -amide

The title compound was prepared in a similar manner as described in Example 49. _{MS: C 20 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 415.0,417.0.

標題化合物を、実施例49に記載のものと同様の方法により調製した。MS：C₂₁H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：429.0、430.0。 Example 55
(S) -5-Chloro-thiophene-2-carboxylic acid (1- {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide

The title compound was prepared in a similar manner as described in Example 49. _{MS: C 21 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 429.0,430.0.

標題化合物を、実施例49に記載のものと同様の方法により調製した。MS：C₂₂H₂₃ClN₄O₂Sについて(M+H)⁺としての実測値：443.0、445.0。 Example 56
(S) -5-Chloro-thiophene-2-carboxylic acid (1- {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide

The title compound was prepared in a similar manner as described in Example 49. _{MS: C 22 H 23 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 443.0,445.0.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₁₉H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：405.1、407.1。 Example 57
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 19 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 405.1,407.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₀H₂₁ClN4O₂Sについて(M+H)+としての実測値：417.1、419.1。 Example 58
5-chloro-thiophene-2-carboxylic acid {5-methyl-3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro-isoxazole -5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. MS: C ₂₀ H ₂₁ ClN4O for ₂ S (M + H) + as the measured value: 417.1,419.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₁H₂₃ClN₄O₂Sについて(M+H)+としての実測値：431.1、433.1。 Example 59
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 21 H 23 ClN 4} O 2 for S (M + H) + as the measured value: 431.1,433.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₂H₂₅ClN₄O₂Sについて(M+H)+としての実測値：445.1、447.1。 Example 60
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 22 H 25 ClN 4} O 2 for S (M + H) + as the measured value: 445.1,447.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₅H₂₉ClN₄O₄Sについて(M+H)+としての実測値：517.1、519.1。 Example 61
1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -5-methyl-4,5-dihydro-isoxazol-3-yl) -phenyl] -imino -Methyl} -piperidine-4-carboxylic acid ethyl ester

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 25 H 29 ClN 4} O 4 for S (M + H) + as the measured value: 517.1,519.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₀H₂₁ClN₄O₂Sについて(M+H)+としての実測値：418.0、420.0。 Example 62
5-Chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-imino-methyl) -phenyl] -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 20 H 21 ClN 4} O 2 for S (M + H) + as the measured value: 418.0,420.0.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₃H₂₆ClN₄O₂Sについて(M+H)+としての実測値：457.1、459.1。 Example 63
5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-azetidin-1-ylidene-methyl) -phenyl] -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl } -Amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 23 H 26 ClN 4} O 2 for S (M + H) + as the measured value: 457.1,459.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₀H₂₃ClN₄O₂Sについて(M+H)⁺としての実測値：419.1、421.1。 Example 64
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N-ethyl-N-methyl-carbamimidoyl) -phenyl] -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl} -Amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 20 H 23 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 419.1,421.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₂H₂₈ClN₅O₂Sについて(M+H)⁺としての実測値：462.1、464.1。 Example 65
5-Chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-dimethylamino-ethyl) -N-methyl-carbamimidoyl] -phenyl} -5-methyl-4,5-dihydro -Isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 8. MS: C ₂₂ H ₂₈ ClN about _{5 O 2 S (M + H} ) + as the measured value: 462.1,464.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₁H₂₅ClN₄O₃Sについて(M+H)+としての実測値：449.1、451.1。 Example 66
5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-methoxy-ethyl) -N-methyl-carbamimidoyl] -phenyl} -5-methyl-4,5-dihydro- Isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 21 H 25 ClN 4} O 3 for S (M + H) + as the measured value: 449.1,451.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₁H₂₅ClN₄O₃Sについて(M+H)+としての実測値：444.1、446.1。 Example 67
5-chloro-thiophene-2-carboxylic acid {3- [4- (N-furan-2-ylmethyl-N-methyl-carbamimidoyl) -phenyl] -5-methyl-4,5-dihydro-isoxazole- 5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 21 H 25 ClN 4} O 3 for S (M + H) + as the measured value: 444.1,446.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₂₃H₂₆ClN₅O₃Sについて(M+H)+としての実測値：488.1、490.1。 Example 68
1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -5-methyl-4,5-dihydro-isoxazol-3-yl) -phenyl] -imino -Methyl} -piperidine-4-carboxylic acid amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 23 H 26 ClN 5} O 3 for S (M + H) + as the measured value: 488.1,490.1.

標題化合物を、実施例8に記載のものと同様の方法により調製した。MS：C₁₈H₁₉ClN₄O₂Sについて(M+H)+としての実測値：391.1、393.1。 Example 69
5-chloro-thiophene-2-carboxylic acid {5-methyl-3- [4- (N-methylcarbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 8. _{MS: C 18 H 19 ClN 4} O 2 for S (M + H) + as the measured value: 391.1,393.1.

Scheme 3

段階1：
カルボン酸17(20.18g、138mmol)を150mLのTHFで溶解し、0℃まで冷却した。溶液を撹拌し、これにBH₃-S(CH₃)₂複合体(26mL、276mmol)をゆっくり加えたところ、激しい反応と著しいガスの発生が起こった。冷却浴を取り除き、反応混合物を室温で2時間撹拌し、その時点でTLCおよびHPLCにより出発原料の消費が確認された。水をゆっくり加えて反応停止し(激しい発熱)、次いで粗製混合物を濃縮し、酢酸エチルで希釈してろ過した。ろ液を濃縮乾固し、所望のアルコール(18)を白色固体で得た(17g、93％)。

Example 70
5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl}- Amide

Stage 1:
Carboxylic acid 17 (20.18 g, 138 mmol) was dissolved in 150 mL of THF and cooled to 0 ° C. The solution was stirred and to this was slowly added BH ₃ —S (CH ₃ ) ₂ complex (26 mL, 276 mmol) resulting in vigorous reaction and significant gas evolution. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours, at which point consumption of starting material was confirmed by TLC and HPLC. The reaction was quenched by the slow addition of water (violent exotherm), then the crude mixture was concentrated, diluted with ethyl acetate and filtered. The filtrate was concentrated to dryness to give the desired alcohol (18) as a white solid (17 g, 93%).

Stage 2:
Benzyl alcohol 18 (17 g, 129 mmol) was dissolved in 300 mL dichloromethane and then treated with 33 g celite followed by PCC (33 g, 155 mmol) to give a dark brown suspension, which was stirred vigorously. After stirring for 3 hours, the reaction was complete by TLC, filtered through a short silica gel pad (2 in. × 5 in.) And slowly eluted with dichloromethane. The filtrate was concentrated to give the desired aldehyde (19) as a white solid (15.62 g, 93%).

Stage 3:
Performed in the same manner as Example 1, Step 1.

Stage 4:
Performed in the same manner as Example 1, Step 2.

Stage 5:
Performed in the same manner as Example 1, Step 5.

Stage 6:
Performed in the same manner as Example 8. _{MS: C 19 H 16 ClFN 4} O 2 for S (M ⁺ H) + as the measured value: 419.1,421.1.

標題化合物を、実施例70に記載のものと同様の方法により調製した。MS：C₂₀H₁₈ClFN₄O₂Sについて(M+H)+としての実測値：433.0、435.0。 Example 71
5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 70. _{MS: C 20 H 18 ClFN 4} O 2 for S (M + H) + as the measured value: 433.0,435.0.

標題化合物を、実施例70に記載のものと同様の方法により調製した。MS：C₂₁H₂₀ClFN₄O₂Sについて(M+H)+としての実測値：447.0、449.0。 Example 72
5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 70. _{MS: C 21 H 20 ClFN 4} O 2 for S (M + H) + as the measured value: 447.0,449.0.

標題化合物を、実施例70に記載のものと同様の方法により調製した。MS：C₁₈H₁₆ClFN₄O₂Sについて(M+H)+としての実測値：407.0、409.0。 Example 73
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-fluoro-phenyl] -dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 70. _{MS: C 18 H 16 ClFN 4} O 2 for S (M + H) + as the measured value: 407.0,409.0.

ニトリル(実施例70、段階5)(0.090g、0.248mmol)およびジメチルアミン(0.28ml、2.0Mテトラヒドロフラン溶液)のジメチルスルホキシド(5mL)溶液を、還流冷却器を備えたフラスコ中、ジイソプロピルエチルアミン(0.08ml、0.58mmol)で処理した。混合物を終夜加熱還流した。翌日、反応をTLCでチェックし、出発原料の完全な消費と、新しい極性スポットが確認された。粗製反応混合物をシリカゲルプラグに吸着させ、ジクロロメタンで溶出して、置換ジメチルアミノ化合物を主生成物として得た。生成物を実施例8の方法で処理し、標題化合物を得た。MS：C₂₀H₂₄ClN₅O₂Sについて(M+H)+としての実測値：434.1、436.0。 Example 74
5-Chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl}- Amide

A solution of nitrile (Example 70, Step 5) (0.090 g, 0.248 mmol) and dimethylamine (0.28 ml, 2.0 M tetrahydrofuran solution) in dimethyl sulfoxide (5 mL) was added to diisopropylethylamine (0.08 g) in a flask equipped with a reflux condenser. ml, 0.58 mmol). The mixture was heated to reflux overnight. The next day, the reaction was checked by TLC, confirming complete consumption of starting material and a new polar spot. The crude reaction mixture was adsorbed onto a silica gel plug and eluted with dichloromethane to give the substituted dimethylamino compound as the main product. The product was treated by the method of Example 8 to give the title compound. MS: C ₂₀ H ₂₄ ClN about _{5 O 2 S (M + H} ) + as the measured value: 434.1,436.0.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₁H₂₄ClN₅O₂Sについて(M+H)+としての実測値：446.1、448.1。 Example 75
5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro- Isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₁ H ₂₄ ClN about _{5 O 2 S (M + H} ) + as the measured value: 446.1,448.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₂H₂₆ClN₅O₂Sについて(M+H)+としての実測値：460.1、462.1。 Example 76
5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₂ H ₂₆ ClN about _{5 O 2 S (M + H} ) + as the measured value: 460.1,462.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₃H₂₈ClN₅O₂Sについて(M+H)+としての実測値：474.1、476.1。 Example 77
5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (imino-piperidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₃ H ₂₈ ClN about _{5 O 2 S (M + H} ) + as the measured value: 474.1,476.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₂H₂₆ClN₅O₂Sについて(M+H)+としての実測値：460.1、462.1。 Example 78
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-pyrrolidin-1-yl-phenyl] -4,5-dihydro-isoxazole-5- Ilmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₂ H ₂₆ ClN about _{5 O 2 S (M + H} ) + as the measured value: 460.1,462.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₃H₂₆ClN₅O₂Sについて(M+H)+としての実測値：472.1、474.1。 Example 79
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-pyrrolidin-1-yl-phenyl] -4,5 -Dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₃ H ₂₆ ClN about _{5 O 2 S (M + H} ) + as the measured value: 472.1,474.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₄H₂₈ClN₅O₂Sについて(M+H)+としての実測値：486.1、488.1。 Example 80
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-pyrrolidin-1-yl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₄ H ₂₈ ClN about _{5 O 2 S (M + H} ) + as the measured value: 486.1,488.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₅H₃₀ClN₅O₂Sについて(M+H)+としての実測値：500.1、502.1。 Example 81
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-pyrrolidin-1-yl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₅ H ₃₀ ClN about _{5 O 2 S (M + H} ) + as the measured value: 500.1,502.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₂H₂₆ClN₅O₃Sについて(M+H)+としての実測値：474.1、476.1。 Example 82
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-morpholin-4-yl-phenyl] -4,5-dihydro-isoxazole-5- Ilmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. _{MS: C 22 H 26 ClN 5} O 3 for S (M + H) + as the measured value: 474.1,476.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₃H₂₆ClN₅O₃Sについて(M+H)+としての実測値：486.1、488.1。 Example 83
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-morpholin-4-yl-phenyl] -4,5 -Dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. _{MS: C 23 H 26 ClN 5} O 3 for S (M + H) + as the measured value: 486.1,488.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₄H₂₈ClN₅O₃Sについて(M+H)+としての実測値：500.1、502.1。 Example 84
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-morpholin-4-yl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide

The title compound was prepared in a similar manner as described in Example 74. _{MS: C 24 H 28 ClN 5} O 3 for S (M + H) + as the measured value: 500.1,502.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₅H₃₀ClN₅O₃Sについて(M+H)+としての実測値：514.1、516.1。 Example 85
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-morpholin-4-yl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide

The title compound was prepared in a similar manner as described in Example 74. _{MS: C 25 H 30 ClN 5} O 3 for S (M + H) + as the measured value: 514.1,516.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₂H₂₈ClN₅O₃Sについて(M+H)+としての実測値：478.1、480.1。 Example 86
5-chloro-thiophene-2-carboxylic acid (3- {4- (N, N-dimethyl-carbamimidoyl) -2-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -4, 5-Dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 74. _{MS: C 22 H 28 ClN 5} O 3 for S (M + H) + as the measured value: 478.1,480.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₃H₂₈ClN₅O₃Sについて(M+H)+としての実測値：490.1、492.1。 Example 87
5-Chloro-thiophene-2-carboxylic acid {3- [2-[(2-methoxy-ethyl) -methyl-amino] -4- (1-methyl-4,5-dihydro-IH-imidazol-2-yl ) -Phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. _{MS: C 23 H 28 ClN 5} O 3 for S (M + H) + as the measured value: 490.1,492.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₄H₃₀ClN₅O₃Sについて(M+H)+としての実測値：504.1、506.1。 Example 88
5-chloro-thiophene-2-carboxylic acid (3- {4- (imino-pyrrolidin-1-yl-methyl) -2-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -4,5 -Dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 74. _{MS: C 24 H 30 ClN 5} O 3 for S (M + H) + as the measured value: 504.1,506.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₅H₃₂ClN₅O₃Sについて(M+H)+としての実測値：518.1、520.2。 Example 89
5-chloro-thiophene-2-carboxylic acid (3- {4- (imino-piperidin-1-yl-methyl) -2-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -4,5 -Dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 74. _{MS: C 25 H 32 ClN 5} O 3 for S (M + H) + as the measured value: 518.1,520.2.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₄H₃₀ClN₅O₂Sについて(M+H)+としての実測値：489.2、491.2。 Example 90
5-Chloro-thiophene-2-carboxylic acid {3- [2-azepan-1-yl-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazole-5- Ilmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₄ H ₃₀ ClN about _{5 O 2 S (M + H} ) + as the measured value: 489.2,491.2.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₅H₃₀ClN₅O₂Sについて(M+H)+としての実測値：501.1、503.1。 Example 91
5-chloro-thiophene-2-carboxylic acid {3- [2-azepan-1-yl-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5 -Dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₅ H ₃₀ ClN about _{5 O 2 S (M + H} ) + as the measured value: 501.1,503.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₆H₃₂ClN₅O₂Sについて(M+H)+としての実測値：515.1、517.1。 Example 92
5-chloro-thiophene-2-carboxylic acid {3- [2-azepan-1-yl-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₆ H ₃₂ ClN about _{5 O 2 S (M + H} ) + as the measured value: 515.1,517.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₇H₃₄ClN₅O₂Sについて(M+H)+としての実測値：529.2、531.2。 Example 93
5-chloro-thiophene-2-carboxylic acid {3- [2-azepan-1-yl-4- (imino-piperidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl } -Amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₇ H ₃₄ ClN about _{5 O 2 S (M + H} ) + as the measured value: 529.2,531.2.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₀H₂₂ClN₅O₂Sについて(M+H)+としての実測値：432.1、434.1。 Example 94
5-Chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₀ H ₂₂ ClN about _{5 O 2 S (M + H} ) + as the measured value: 432.1,434.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₁H₂₂ClN₅O₂Sについて(M+H)+としての実測値：444.1、446.1。 Example 95
5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl) -Amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₁ H ₂₂ ClN about _{5 O 2 S (M + H} ) + as the measured value: 444.1,446.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₂H₂₄ClN₅O₂Sについて(M+H)+としての実測値：458.1、460.1。 Example 96
5-Chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₂ H ₂₄ ClN about _{5 O 2 S (M + H} ) + as the measured value: 458.1,460.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₃H₂₆ClN₅O₂Sについて(M+H)⁺としての実測値：472.1、474.1。 Example 97
5-Chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. MS: C ₂₃ H ₂₆ ClN about _{5 O 2 S (M + H} ) + as the measured value: 472.1,474.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₂H₂₄ClN₅O₃Sについて(M+H)⁺としての実測値：474.1、476.1。 Example 98
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-morpholin-4-yl-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. _{MS: C 22 H 24 ClN 5} O 3 for S (M ⁺ H) + as the measured value: 474.1,476.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₃H₂₄ClN₅O₃Sについて(M+H)+としての実測値：486.1、488.1。 Example 99
5-Chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-morpholin-4-yl-phenyl] -isoxazole-5 -Ilmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. _{MS: C 23 H 24 ClN 5} O 3 for S (M + H) + as the measured value: 486.1,488.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₄H₂₆ClN₅O₃Sについて(M+H)+としての実測値：500.1、502.1。 Example 100
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-morpholin-4-yl-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. _{MS: C 24 H 26 ClN 5} O 3 for S (M + H) + as the measured value: 500.1,502.1.

標題化合物を、実施例74に記載のものと同様の方法により調製した。MS：C₂₅H₂₈ClN₅O₃Sについて(M+H)+としての実測値：514.1、516.1。 Example 101
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-morpholin-4-yl-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 74. _{MS: C 25 H 28 ClN 5} O 3 for S (M + H) + as the measured value: 514.1,516.1.

ニトリル化合物(実施例70、段階5)(0.264g、0.727mmol)のジメチルスルホキシド溶液をナトリウムメトキシド(0.086g、1.60mmol)で処理した。混合物を室温で2時間撹拌し、TLCでチェックして、出発原料の完全な消費と、新しい極性スポットが確認された。粗製反応混合物をシリカゲルプラグに吸着させ、ジクロロメタンで溶出して、置換メトキシ化合物を主生成物として得た。生成物を実施例8に記載のものと同様の方法で処理し、標題化合物を得た。MS：C19H21ClN4O3Sについて(M+H)+としての実測値：421.0、423.0。 Example 102
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-methoxy-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

A solution of the nitrile compound (Example 70, Step 5) (0.264 g, 0.727 mmol) in dimethyl sulfoxide was treated with sodium methoxide (0.086 g, 1.60 mmol). The mixture was stirred at room temperature for 2 hours and checked by TLC to confirm complete consumption of starting material and a new polar spot. The crude reaction mixture was adsorbed onto a silica gel plug and eluted with dichloromethane to give the substituted methoxy compound as the main product. The product was treated in a similar manner as described in Example 8 to give the title compound. MS: Found for C19H21ClN4O3S as (M + H) +: 421.0, 423.0.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₀H₂₁ClN₄O₃Sについて(M+H)+としての実測値：433.0、435.0。 Example 103
5-chloro-thiophene-2-carboxylic acid {3- [2-methoxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro-isoxazole -5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 20 H 21 ClN 4} O 3 for S (M + H) + as the measured value: 433.0,435.0.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₁H₂₃ClN₄O₃Sについて(M+H)+としての実測値：447.1、449.1。 Example 104
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-methoxy-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 21 H 23 ClN 4} O 3 for S (M + H) + as the measured value: 447.1,449.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₂H₂₅ClN₄O₃Sについて(M+H)+としての実測値：461.1、463.1。 Example 105
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-methoxy-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 22 H 25 ClN 4} O 3 for S (M + H) + as the measured value: 461.1,463.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₀H₂₃ClN₄O₃Sについて(M+H)+としての実測値：435.1、437.1。 Example 106
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-ethoxy-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 20 H 23 ClN 4} O 3 for S (M + H) + as the measured value: 435.1,437.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₁H₂₃ClN₄O₃Sについて(M+H)+としての実測値：447.1、449.1。 Example 107
5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro-isoxazole -5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 21 H 23 ClN 4} O 3 for S (M + H) + as the measured value: 447.1,449.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₂H₂₅ClN₄O₃Sについて(M+H)+としての実測値：461.1、463.1。 Example 108
5-Chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 22 H 25 ClN 4} O 3 for S (M + H) + as the measured value: 461.1,463.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₁H₂5ClN₄O₃Sについて(M+H)+としての実測値：449.1、451.1。 Example 109
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-isopropoxy-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl}- Amide

The title compound was prepared by a method similar to that described in Example 102. MS: Found for (C + H) + for C ₂₁ H ₂ 5ClN ₄ O ₃ S: 449.1, 451.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₂H₂₅ClN₄O₃Sについて(M+H)+としての実測値：461.1、463.1。 Example 110
5-chloro-thiophene-2-carboxylic acid {3- [2-isopropoxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro- Isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 22 H 25 ClN 4} O 3 for S (M + H) + as the measured value: 461.1,463.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₃H₂₇ClN₄O₃Sについて(M+H)+としての実測値：475.1、477.1。 Example 111
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-isopropoxy-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 23 H 27 ClN 4} O 3 for S (M + H) + as the measured value: 475.1,477.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₃H₂₇ClN₄O₃Sについて(M+H)+としての実測値：475.5、477.5。 Example 112
5-Chloro-thiophene-2-carboxylic acid {3- [2-cyclopentyloxy-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl}- Amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 23 H 27 ClN 4} O 3 for S (M + H) + as the measured value: 475.5,477.5.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₄H₂₇ClN₄O₃Sについて(M+H)+としての実測値：487.5、489.5。 Example 113
5-chloro-thiophene-2-carboxylic acid {3- [2-cyclopentyloxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro- Isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 24 H 27 ClN 4} O 3 for S (M + H) + as the measured value: 487.5,489.5.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₅H₂₉ClN₄O₃Sについて(M+H)+としての実測値：501.6、503.6。 Example 114
5-chloro-thiophene-2-carboxylic acid {3- [2-cyclopentyloxy-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 25 H 29 ClN 4} O 3 for S (M + H) + as the measured value: 501.6,503.6.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₄H₂₉ClN₄O₃Sについて(M+H)+としての実測値：489.6、491.6。 Example 115
5-Chloro-thiophene-2-carboxylic acid {3- [2-cyclohexyloxy-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl}- Amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 24 H 29 ClN 4} O 3 for S (M + H) + as the measured value: 489.6,491.6.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₅H₂₉ClN₄O₃Sについて(M+H)+としての実測値：501.6、503.6。 Example 116
5-chloro-thiophene-2-carboxylic acid {3- [2-cyclohexyloxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro- Isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 25 H 29 ClN 4} O 3 for S (M + H) + as the measured value: 501.6,503.6.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₆H₃₁ClN₄O₃Sについて(M+H)+としての実測値：515.6、517.6。 Example 117
5-chloro-thiophene-2-carboxylic acid {3- [2-cyclohexyloxy-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 26 H 31 ClN 4} O 3 for S (M + H) + as the measured value: 515.6,517.6.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₁₉H₁₉ClN₄O₃Sについて(M+H)+としての実測値：419.0、421.0。 Example 118
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-methoxy-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 19 H 19 ClN 4} O 3 for S (M + H) + as the measured value: 419.0,421.0.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClN₄O₃Sについて(M+H)+としての実測値：431.0、433.0。 Example 119
5-chloro-thiophene-2-carboxylic acid {3- [2-methoxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl}- Amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 20 H 19 ClN 4} O 3 for S (M + H) + as measured value: 431.0,433.0.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₁H₂₁ClN₄O₃Sについて(M+H)+としての実測値：445.0、447.1。 Example 120
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-methoxy-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 21 H 21 ClN 4} O 3 for S (M + H) + as the measured value: 445.0,447.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₂H₂₃ClN₄O₃Sについて(M+H)+としての実測値：459.1、461.1。 Example 121
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-methoxy-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 22 H 23 ClN 4} O 3 for S (M + H) + as the measured value: 459.1,461.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₀H₂₁ClN₄O₃Sについて(M+H)+としての実測値：433.1、435.1。 Example 122
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-ethoxy-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 20 H 21 ClN 4} O 3 for S (M + H) + as the measured value: 433.1,435.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₁H₂₁ClN₄O₃Sについて(M+H)+としての実測値：445.1、447.1。 Example 123
5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl}- Amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 21 H 21 ClN 4} O 3 for S (M + H) + as the measured value: 445.1,447.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₂H₂₃ClN₄O₃Sについて(M+H)+としての実測値：459.1、461.1。 Example 124
5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 22 H 23 ClN 4} O 3 for S (M + H) + as the measured value: 459.1,461.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₃H₂₅ClN₄O₃Sについて(M+H)+としての実測値：473.1、475.1。 Example 125
5-Chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 23 H 25 ClN 4} O 3 for S (M + H) + as the measured value: 473.1,475.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₃H₂₅ClN₄O₃Sについて(M+H)+としての実測値：447.1、449.1。 Example 126
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-isopropoxy-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 23 H 25 ClN 4} O 3 for S (M + H) + as the measured value: 447.1,449.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₂H₂₃ClN₄O₃Sについて(M+H)+としての実測値：459.1、461.1。 Example 127
5-Chloro-thiophene-2-carboxylic acid {3- [2-Isopropoxy-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -Amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 22 H 23 ClN 4} O 3 for S (M + H) + as the measured value: 459.1,461.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₃H₂₅ClN₄O₃Sについて(M+H)+としての実測値：473.1、475.1。 Example 128
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-isopropoxy-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 23 H 25 ClN 4} O 3 for S (M + H) + as the measured value: 473.1,475.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₄H₂₇ClN₄O₃Sについて(M+H)+としての実測値：487.1、489.1。 Example 129
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-isopropoxy-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 24 H 27 ClN 4} O 3 for S (M + H) + as the measured value: 487.1,489.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₄H₂₁ClN₄O₃Sについて(M+H)+としての実測値：511.1、513.1。 Example 130
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-phenoxy-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 24 H 21 ClN 4} O 3 for S (M + H) + as the measured value: 511.1,513.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₄H₂₁ClN₄O₃Sについて(M+H)+としての実測値：523.1、525.1。 Example 131
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-phenoxy-phenyl] -isoxazol-5-ylmethyl}- Amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 24 H 21 ClN 4} O 3 for S (M + H) + as the measured value: 523.1,525.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₆H₂₃ClN₄O₃Sについて(M+H)+としての実測値：537.1、539.1。 Example 132
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-phenoxy-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 26 H 23 ClN 4} O 3 for S (M + H) + as the measured value: 537.1,539.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₅H₂₃ClN₄O₄Sについて(M+H)+としての実測値：481.1、483.1。 Example 133
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2- (4-methoxy-phenoxy) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 25 H 23 ClN 4} O 4 for S (M + H) + as the measured value: 481.1,483.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₆H₂₃ClN₄O₄Sについて(M+H)+としての実測値：493.1、495.1。 Example 134
5-Chloro-thiophene-2-carboxylic acid {3- [2- (4-methoxy-phenoxy) -4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazole -5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 26 H 23 ClN 4} O 4 for S (M + H) + as the measured value: 493.1,495.1.

標題化合物を、実施例102に記載のものと同様の方法により調製した。MS：C₂₇H₂₅ClN₄O₄Sについて(M+H)+としての実測値：507.1、509.1。 Example 135
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2- (4-methoxy-phenoxy) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 102. _{MS: C 27 H 25 ClN 4} O 4 for S (M + H) + as the measured value: 507.1,509.1.

標題化合物を、実施例102に記載のものと同様の方法により、ナトリウムメトキシドの代わりにナトリウムチオメトキシドを用いて調製した。MS：C₁₉H₂₁ClN₄O₂S₂について(M+H)+としての実測値：437.0、439.0。 Example 136
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-methylsulfanyl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl}- Amide

The title compound was prepared by a method similar to that described in Example 102 using sodium thiomethoxide instead of sodium methoxide. _{MS: C 19 H 21 ClN 4} O 2 for S ₂ (M + H) + as the measured value: 437.0,439.0.

標題化合物を、実施例136に記載のものと同様の方法により調製した。MS：C₂₀H₂₁ClN₄O₂S₂について(M+H)+としての実測値：449.0、451.0。 Example 137
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-methylsulfanyl-phenyl] -4,5-dihydro- Isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 136. _{MS: C 20 H 21 ClN 4} O 2 for S ₂ (M + H) + as the measured value: 449.0,451.0.

標題化合物を、実施例136に記載のものと同様の方法により調製した。MS：C₂₁H₂₃ClN₄O₂S₂について(M+H)+としての実測値：463.0、465.1。 Example 138
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-methylsulfanyl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 136. _{MS: C 21 H 23 ClN 4} O 2 for S ₂ (M + H) + as the measured value: 463.0,465.1.

標題化合物を、実施例136に記載のものと同様の方法により調製した。MS：C₂₂H₂₅ClN₄O₂S₂について(M+H)+としての実測値：477.0、479.1。 Example 139
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-methylsulfanyl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 136. _{MS: C 22 H 25 ClN 4} O 2 for S ₂ (M + H) + as the measured value: 477.0,479.1.

標題化合物を、実施例136に記載のものと同様の方法により調製した。MS：C₁₉H₁₉ClN₄O₂S₂について(M+H)+としての実測値：435.0、437.0。 Example 140
5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-methylsulfanyl-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 136. _{MS: C 19 H 19 ClN 4} O 2 for S ₂ (M + H) + as the measured value: 435.0,437.0.

標題化合物を、実施例136に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClN₄O₂S₂について(M+H)+としての実測値：447.0、449.0。 Example 141
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-methylsulfanyl-phenyl] -isoxazol-5-ylmethyl} -Amide

The title compound was prepared by a method similar to that described in Example 136. _{MS: C 20 H 19 ClN 4} O 2 for S ₂ (M + H) + as the measured value: 447.0,449.0.

標題化合物を、実施例136に記載のものと同様の方法により調製した。MS：C₂₁H₂₁ClN₄O₂S₂について(M+H)+としての実測値：461.0、463.0。 Example 142
5-Chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-methylsulfanyl-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 136. _{MS: C 21 H 21 ClN 4} O 2 for S ₂ (M + H) + as the measured value: 461.0,463.0.

標題化合物を、実施例136に記載のものと同様の方法により調製した。MS：C₂₂H₂₃ClN₄O₂S₂について(M+H)+としての実測値：475.1、477.0。 Example 143
5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-methylsulfanyl-phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 136. _{MS: C 22 H 23 ClN 4} O 2 for S ₂ (M + H) + as the measured value: 475.1,477.0.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₅H₁₃ClN₂O₂Sについて(M+H)+としての実測値：321.3、323.3。 Example 144
5-Chloro-thiophene-2-carboxylic acid (3-phenyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared by a method similar to that described in Example 1. MS: C ₁₅ H ₁₃ ClN about _{2 O 2 S (M + H} ) + as the measured value: 321.3,323.3.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₆H₁₅ClN₂O₂Sについて(M+H)+としての実測値：335.4、337.3。 Example 145
5-Chloro-thiophene-2-carboxylic acid (5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared by a method similar to that described in Example 1. MS: C ₁₆ H ₁₅ ClN about _{2 O 2 S (M + H} ) + as the measured value: 335.4,337.3.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₅H₁₁ClN₂O₂Sについて(M+H)+としての実測値：319.2、321.1。 Example 146
5-Chloro-thiophene-2-carboxylic acid (3-phenyl-isoxazol-5-ylmethyl) -amide

The title compound was prepared by a method similar to that described in Example 1. MS: C ₁₅ H ₁₁ ClN about _{2 O 2 S (M + H} ) + as the measured value: 319.2,321.1.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₆H₁₅ClN₂O₂Sについて(M+H)+としての実測値：335.2、337.2。 Example 147
5-Chloro-thiophene-2-carboxylic acid (3-p-tolyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared by a method similar to that described in Example 1. MS: C ₁₆ H ₁₅ ClN about _{2 O 2 S (M + H} ) + as the measured value: 335.2,337.2.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₇H₁₇ClN₂O₂Sについて(M+H)+としての実測値：349.2、351.2。 Example 148
5-Chloro-thiophene-2-carboxylic acid (5-methyl-3-p-tolyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared by a method similar to that described in Example 1. MS: C ₁₇ H ₁₇ ClN about _{2 O 2 S (M + H} ) + as the measured value: 349.2,351.2.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₆H₁₃ClN₂O₂Sについて(M+H)+としての実測値：333.2、335.1。 Example 149
5-Chloro-thiophene-2-carboxylic acid (3-p-tolyl-isoxazol-5-ylmethyl) -amide

The title compound was prepared by a method similar to that described in Example 1. MS: C ₁₆ H ₁₃ ClN about _{2 O 2 S (M + H} ) + as the measured value: 333.2,335.1.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₆H₁₅ClN₂O₃Sについて(M+H)+としての実測値：379.2、381.2。 Example 150
5-Chloro-thiophene-2-carboxylic acid [3- (4-methoxy-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 1. _{MS: C 16 H 15 ClN 2} O 3 for S (M + H) + as the measured value: 379.2,381.2.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₇H₁₇ClN₂O₃Sについて(M+H)+としての実測値：393.2、395.1。 Example 151
5-Chloro-thiophene-2-carboxylic acid [3- (4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 1. _{MS: C 17 H 17 ClN 2} O 3 for S (M + H) + as the measured value: 393.2,395.1.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₆H₁₃ClN₂O₃Sについて(M+H)+としての実測値：377.3、379.3。 Example 152
5-Chloro-thiophene-2-carboxylic acid [3- (4-methoxy-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 1. _{MS: C 16 H 13 ClN 2} O 3 for S (M + H) + as the measured value: 377.3,379.3.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₅H₁₂Cl₂N₂O₂Sについて(M+H)+としての実測値：356.7、358.7。 Example 153
5-Chloro-thiophene-2-carboxylic acid [3- (4-chloro-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 1. _{MS: C 15 H 12 Cl 2} N 2 O for ₂ S (M + H) + as the measured value: 356.7,358.7.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₆H₁₄Cl₂N₂O₂Sについて(M+H)+としての実測値：370.7、372.8。 Example 154
5-Chloro-thiophene-2-carboxylic acid [3- (4-chloro-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 1. _{MS: C 16 H 14 Cl 2} N 2 O for ₂ S (M + H) + as the measured value: 370.7,372.8.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₅H₁₀Cl₂N₂O₂Sについて(M+H)+としての実測値：354.8、356.7。 Example 155
5-Chloro-thiophene-2-carboxylic acid [3- (4-chloro-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 1. _{MS: C 15 H 10 Cl 2} N 2 O for ₂ S (M + H) + as the measured value: 354.8,356.7.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₇H₁₅ClN₂O₄Sについて(M+H)+としての実測値：379.4、381.4。 Example 156
4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -benzoic acid methyl ester

The title compound was prepared by a method similar to that described in Example 1. _{MS: C 17 H 15 ClN 2} O 4 for S (M + H) + as the measured value: 379.4,381.4.

標題化合物を、実施例1に記載のものと同様の方法により調製した。MS：C₁₇H₁₃ClN₂O₄Sについて(M+H)+としての実測値：377.3、379.3。 Example 157
4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -isoxazol-3-yl) -benzoic acid methyl ester

The title compound was prepared by a method similar to that described in Example 1. _{MS: C 17 H 13 ClN 2} O 4 for S (M + H) + as the measured value: 377.3,379.3.

メタノールおよび水中の化合物156(0.360g、0.952mmol)の溶液を水酸化リチウム(2.86ml、メタノール中1M)で処理した。混合物を室温で終夜撹拌した。翌日、反応をTLCでチェックし、出発原料の完全な消費と、新しい、極性の高いスポットが確認された。粗製反応混合物をpH=3まで酸性化し、減圧濃縮し、次いで少量のメタノール(約5mL)に懸濁して水で粉砕し、白色固体を得た。固体をろ過して乾燥し、所望の生成物を得た。MS：C₁₆H₁₃ClN₂O₄Sについて(M+H)+としての実測値：365.3、367.3。 Example 158
4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -benzoic acid

A solution of compound 156 (0.360 g, 0.952 mmol) in methanol and water was treated with lithium hydroxide (2.86 ml, 1M in methanol). The mixture was stirred at room temperature overnight. The next day, the reaction was checked by TLC, confirming complete consumption of starting material and a new, more polar spot. The crude reaction mixture was acidified to pH = 3, concentrated under reduced pressure, then suspended in a small amount of methanol (ca. 5 mL) and triturated with water to give a white solid. The solid was filtered and dried to give the desired product. _{MS: C 16 H 13 ClN 2} O 4 for S (M + H) + as the measured value: 365.3,367.3.

標題化合物を、実施例158に記載のものと同様の方法により調製した。MS：C₁₆H₁₁ClN₂O₄Sについて(M+H)+としての実測値：363.4、365.4。 Example 159
4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -isoxazol-3-yl) -benzoic acid

The title compound was prepared in a similar manner as described in Example 158. _{MS: C 16 H 11 ClN 2} O 4 for S (M + H) + as the measured value: 363.4,365.4.

ニトロイソキサゾリン(実施例1と同様の様式で4-ニトロベンズアルデヒドから調製)(0.078g、0.214mmol)のエタノール溶液を塩化スズ2水和物(0.155g、0.684mmol)で処理した。混合物を2時間加熱還流した。反応をTLCでチェックして、出発原料の完全な消費と、新しい、極性の低いスポットが確認された。粗製反応混合物を飽和炭酸カリウムで希釈し、約30分間撹拌し、次いでセライトパッドを通してろ過した。ろ液を濃縮して所望の生成物を得、これを調製用HPLCで精製した。MS：C₁₅H₁₄ClN₃O₂Sについて(M+H)+としての実測値：336.3、338.3。 Example 160
5-Chloro-thiophene-2-carboxylic acid [3- (4-amino-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

A solution of nitroisoxazoline (prepared from 4-nitrobenzaldehyde in the same manner as Example 1) (0.078 g, 0.214 mmol) in ethanol was treated with tin chloride dihydrate (0.155 g, 0.684 mmol). The mixture was heated to reflux for 2 hours. The reaction was checked by TLC and confirmed complete consumption of starting material and a new, less polar spot. The crude reaction mixture was diluted with saturated potassium carbonate, stirred for about 30 minutes, and then filtered through a celite pad. The filtrate was concentrated to give the desired product, which was purified by preparative HPLC. _{MS: C 15 H 14 ClN 3} O 2 for S (M + H) + as the measured value: 336.3,338.3.

標題化合物を、実施例160に記載のものと同様の方法により調製した。MS：C₁₅H₁₂ClN₃O₂Sについて(M+H)+としての実測値：334.3、336.3。 Example 161
5-Chloro-thiophene-2-carboxylic acid [3- (4-amino-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared in a similar manner as described in Example 160. _{MS: C 15 H 12 ClN 3} O 2 for S (M + H) + as the measured value: 334.3,336.3.

酸化合物158(0.088g、0.243mmol)、ジメチルアミン(0.032ml、0.316mmol)およびトリエチルアミン(0.051ml、0.365mmol)のジメチルホルムアミド溶液を塩化BOP(0.074g、0.292mmol)で処理した。混合物を室温で終夜撹拌した。翌日、反応をTLCでチェックして、出発原料の完全な消費と、新しい、極性の低いスポットが確認された。粗製反応混合物を調製用HPLCで精製して、所望の生成物を得た。MS：C₁₈H₁₈ClN₃O₃Sについて(M+H)+としての実測値：392.5、394.5。 Example 162
5-Chloro-thiophene-2-carboxylic acid [3- (4-dimethylcarbamoyl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

A solution of acid compound 158 (0.088 g, 0.243 mmol), dimethylamine (0.032 ml, 0.316 mmol) and triethylamine (0.051 ml, 0.365 mmol) in dimethylformamide was treated with BOP chloride (0.074 g, 0.292 mmol). The mixture was stirred at room temperature overnight. The next day, the reaction was checked by TLC to confirm complete consumption of starting material and a new, less polar spot. The crude reaction mixture was purified by preparative HPLC to give the desired product. _{MS: C 18 H 18 ClN 3} O 3 for S (M + H) + as the measured value: 392.5,394.5.

標題化合物を、実施例162に記載のものと同様の方法により調製した。MS：C₁₉H₁₈ClN₃O₃Sについて(M+H)+としての実測値：404.3、406.3。 Example 163
5-Chloro-thiophene-2-carboxylic acid {3- [4- (azetidine-1-carbonyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 162. _{MS: C 19 H 18 ClN 3} O 3 for S (M + H) + as the measured value: 404.3,406.3.

標題化合物を、実施例162に記載のものと同様の方法により調製した。MS：C₂₀H₂₀ClN₃O₃Sについて(M+H)+としての実測値：418.0、420.0。 Example 164
5-Chloro-thiophene-2-carboxylic acid {3- [4- (pyrrolidine-1-carbonyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 162. _{MS: C 20 H 20 ClN 3} O 3 for S (M + H) + as the measured value: 418.0,420.0.

標題化合物を、実施例162に記載のものと同様の方法により調製した。MS：C₂₁H₂₂ClN₃O₃Sについて(M+H)+としての実測値：432.3、434.3。 Example 165
5-chloro-thiophene-2-carboxylic acid {3- [4- (2-methyl-pyrrolidine-1-carbonyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 162. _{MS: C 21 H 22 ClN 3} O 3 for S (M + H) + as the measured value: 432.3,434.3.

標題化合物を、実施例162に記載のものと同様の方法により調製した。MS：C₂₃H₂₉ClN₄O₃Sについて(M+H)+としての実測値：477.2、479.1。 Example 166
5-Chloro-thiophene-2-carboxylic acid (3- {4-[(2-diethylamino-ethyl) -methyl-carbamoyl] -phenyl} -4,5-dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared by a method similar to that described in Example 162. _{MS: C 23 H 29 ClN 4} O 3 for S (M + H) + as the measured value: 477.2,479.1.

標題化合物を、実施例162に記載のものと同様の方法により調製した。MS：C₂₀H₁₈ClN₃O₃Sについて(M+H)+としての実測値：416.1、418.0。 Example 167
5-Chloro-thiophene-2-carboxylic acid {3- [4- (pyrrolidine-1-carbonyl) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 162. _{MS: C 20 H 18 ClN 3} O 3 for S (M + H) + as the measured value: 416.1,418.0.

標題化合物を、実施例162に記載のものと同様の方法により調製した。MS：C₂₀H₁₈ClN₃O₃Sについて(M+H)+としての実測値：475.1、477.1。 Example 168
5-Chloro-thiophene-2-carboxylic acid (3- {4-[(2-diethylamino-ethyl) -methyl-carbamoyl] -phenyl} -isoxazol-5-ylmethyl) -amide

The title compound was prepared by a method similar to that described in Example 162. _{MS: C 20 H 18 ClN 3} O 3 for S (M + H) + as the measured value: 475.1,477.1.

Scheme 4

段階1：
イソネペコチン酸エチル、24(9.8mL、64mmol)をジクロロメタン(100mL)で希釈して、ピロ炭酸t-ブチル(16mL、70mmol)で処理したところ、著しいガスの発生が起こった。20分後、澄明溶液をTLC(ジクロロメタン)でチェックして、出発原料アミンの完全な消費が確認された。反応混合物を濃縮して、少量のt-ブタノールを含む保護アミン(25)を無色油状物で得た。

Example 169
5-Chloro-thiophene-2-carboxylic acid [3- (1-ethyl-piperidin-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide (31).

Stage 1:
When ethyl isonepecotate, 24 (9.8 mL, 64 mmol) was diluted with dichloromethane (100 mL) and treated with t-butyl pyrocarbonate (16 mL, 70 mmol), significant gas evolution occurred. After 20 minutes, the clear solution was checked with TLC (dichloromethane) to confirm complete consumption of starting amine. The reaction mixture was concentrated to give the protected amine (25) containing a small amount of t-butanol as a colorless oil.

Stage 2:
Performed in the same manner as Example 49, Step 1.

Stage 3:
Performed in the same manner as Example 1, Step 1.

Stage 4:
Performed in the same manner as Example 1, Step 2. This material was not purified or characterized and was used immediately for Step 5.

Stage 5:
Performed in the same manner as Example 1, Step 5.

Stage 6:
Performed in the same manner as Example 49, Step 5. _{MS: C 14 H 18 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 328.1,330.1.

Stage 7:
Amine hydrochloride 30 (40 mg, 0.11 mmol) was diluted with 4 mL dichloroethane and then treated with 5 drops of acetaldehyde, triethylamine (18 uL, 0.13 mmol) and Na (OAc) ₃ BH (47 mg, 0.22 mmol). A slightly turbid mixture was obtained, which was stirred overnight. The next day, the reaction was checked by HPLC and confirmed to be complete. This was then concentrated and purified by preparative HPLC to give the desired tertiary amine salt as a white solid. _{MS: C 16 H 22 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 356.4,358.4.

標題化合物を、実施例169に記載のものと同様の方法により調製した。MS：C₂₁H₂₄ClN₃O₂Sについて(M+H)⁺としての実測値：418.6、420.6。 Example 170
5-Chloro-thiophene-2-carboxylic acid [3- (1-benzyl-piperidin-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 169. _{MS: C 21 H 24 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 418.6,420.6.

標題化合物を、実施例169に記載のものと同様の方法により調製した。MS：C₁₇H₂₄ClN₃O₂Sについて(M+H)⁺としての実測値：370.6、372.5。 Example 171
5-Chloro-thiophene-2-carboxylic acid [3- (1-isopropyl-piperidin-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 169. _{MS: C 17 H 24 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 370.6,372.5.

アミン30(40mg、0.11mmol)をメタノール(5mL)に溶解し、次いでトリエチルアミン(46uL、0.33mmol)および1H-ピラゾール-1-カルボキサミジン(32mg、0.22mmol)で終夜処理した。翌日、反応混合物を濃縮し、粗製反応混合物を逆相HPLCで精製して、所望のグアニジンを白色粉末で得た。MS：C₁₅H₂₀ClN₅O₂Sについて(M+H)⁺としての実測値：370.6、372.4。 Example 172
5-Chloro-thiophene-2-carboxylic acid [3- (1-carbamimidoyl-piperidin-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

Amine 30 (40 mg, 0.11 mmol) was dissolved in methanol (5 mL) and then treated with triethylamine (46 uL, 0.33 mmol) and 1H-pyrazole-1-carboxamidine (32 mg, 0.22 mmol) overnight. The next day, the reaction mixture was concentrated and the crude reaction mixture was purified by reverse phase HPLC to give the desired guanidine as a white powder. MS: C ₁₅ H ₂₀ ClN about _{5 O 2 S (M + H} ) + as the measured value: 370.6,372.4.

アミン30(40mg、0.11mmol)、トリエチルアミン(46uL、0.33mmol)エチルアセトイミデート塩酸塩(27mg、0.22mmol)およびエタノール(5mL)を混合し、次いで得られた混濁白色溶液を終夜撹拌した。翌日、HPLCで反応が起こったことが確認され、濃縮し、調製用HPLCで精製して、所望のアミジンをTFA塩で得た。MS：C₁₆H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：369.5、371.5。 Example 173
5-Chloro-thiophene-2-carboxylic acid {3- [1- (1-Imino-ethyl) -piperidin-4-yl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

Amine 30 (40 mg, 0.11 mmol), triethylamine (46 uL, 0.33 mmol) ethylacetimidate hydrochloride (27 mg, 0.22 mmol) and ethanol (5 mL) were mixed and then the resulting turbid white solution was stirred overnight. The next day, the reaction was confirmed by HPLC, concentrated and purified by preparative HPLC to give the desired amidine as a TFA salt. _{MS: C 16 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 369.5,371.5.

標題化合物を、実施例173に記載のものと同様の方法により調製した。MS：C₂₁H₂₃ClN₄O₂Sについて(M+H)⁺としての実測値：431.5、433.5。 Example 174
5-chloro-thiophene-2-carboxylic acid {3- [1- (imino-phenyl-methyl) -piperidin-4-yl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 173. _{MS: C 21 H 23 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 431.5,433.5.

標題化合物を、実施例173に記載のものと同様の方法により調製した。MS：C₂₀H₂₂ClN₅O₂Sについて(M+H)⁺としての実測値：432.5、434.5。 Example 175
5-Chloro-thiophene-2-carboxylic acid {3- [1- (imino-pyridin-2-yl-methyl) -piperidin-4-yl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 173. MS: C ₂₀ H ₂₂ ClN about _{5 O 2 S (M + H} ) + as the measured value: 432.5,434.5.

標題化合物を、実施例169、段階6に記載のものと同様の方法により調製した。MS：C₁₄H₁₆ClN₃O₂Sについて(M+H)⁺としての実測値：326.0、328.0。 Example 176
5-Chloro-thiophene-2-carboxylic acid (3-piperidin-4-yl-isoxazol-5-ylmethyl) -amide

The title compound was prepared by a method similar to that described in Example 169, Step 6. _{MS: C 14 H 16 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 326.0,328.0.

標題化合物を、実施例169に記載のものと同様の方法により調製した。MS：C₁₆H₂₀ClN₃O₂Sについて(M+H)⁺としての実測値：354.1、356.1。 Example 177
5-Chloro-thiophene-2-carboxylic acid [3- (1-ethyl-piperidin-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 169. _{MS: C 16 H 20 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 354.1,356.1.

標題化合物を、実施例169に記載のものと同様の方法により調製した。MS：C₂₁H₂₂ClN₃O₂Sについて(M+H)⁺としての実測値：416.1、418.1。 Example 178
5-Chloro-thiophene-2-carboxylic acid [3- (1-benzyl-piperidin-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 169. _{MS: C 21 H 22 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 416.1,418.1.

標題化合物を、実施例172に記載のものと同様の方法により調製した。MS：C₁₅H₁₈ClN₅O₂Sについて(M+H)⁺としての実測値：368.0、370.1。 Example 179
5-Chloro-thiophene-2-carboxylic acid [3- (1-carbamimidoyl-piperidin-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 172. MS: C ₁₅ H ₁₈ ClN about _{5 O 2 S (M + H} ) + as the measured value: 368.0,370.1.

標題化合物を、実施例173に記載のものと同様の方法により調製した。MS：C₁₆H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：367.1、369.1。 Example 180
5-Chloro-thiophene-2-carboxylic acid {3- [1- (1-imino-ethyl) -piperidin-4-yl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 173. _{MS: C 16 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 367.1,369.1.

標題化合物を、実施例173に記載のものと同様の方法により調製した。MS：C₂₁H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：429.1、431.1。 Example 181
5-Chloro-thiophene-2-carboxylic acid {3- [1- (imino-phenyl-methyl) -piperidin-4-yl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 173. _{MS: C 21 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 429.1,431.1.

標題化合物を、実施例173に記載のものと同様の方法により調製した。MS：C₁₅H₁₈ClN₅O₂Sについて(M+H)⁺としての実測値：368.1、370.1。 Example 182
5-Chloro-thiophene-2-carboxylic acid [3- (1-carbamimidoyl-piperidin-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 173. MS: C ₁₅ H ₁₈ ClN about _{5 O 2 S (M + H} ) + as the measured value: 368.1,370.1.

臭化アリール(実施例1、200mg、0.50mmol)、2-ホルミルフェニルボロン酸(90mg、0.60mmol)およびK₂CO₃(106mg、1.0mmol)をジグリム(5mL)および水(1mL)で希釈した。混合物を3〜5分間脱気し、次いでPd(PPh₃)₄(58mg、0.05mmol)で処理し、HPLCによりすべての出発原料臭化物の消費が確認されるまで、120℃で加熱した。得られた混合物を水で希釈し、ろ過し、残った固体をシリカゲルクロマトグラフィ(0〜10％酢酸エチル/ジクロロメタン)で精製して、所望のビフェニルアルデヒドを白色固体で得た。MS：C₂₂H₁₇ClN₂O₃Sについて(M+H)+としての実測値：425.4、427.4。 Example 183
5-Chloro-thiophene-2-carboxylic acid [3- (2'-formyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

Aryl bromide (Example 1, 200 mg, 0.50 mmol), 2-formylphenylboronic acid (90 mg, 0.60 mmol) and K ₂ CO ₃ (106 mg, 1.0 mmol) were diluted with diglyme (5 mL) and water (1 mL). . The mixture was degassed for 3-5 minutes, then treated with Pd (PPh ₃ ) ₄ (58 mg, 0.05 mmol) and heated at 120 ° C. until consumption of all starting bromide was confirmed by HPLC. The resulting mixture was diluted with water, filtered, and the remaining solid was purified by silica gel chromatography (0-10% ethyl acetate / dichloromethane) to give the desired biphenylaldehyde as a white solid. _{MS: C 22 H 17 ClN 2} O 3 for S (M + H) + as measured value: 425.4,427.4.

標題化合物を、実施例183に記載のものと同様の方法により調製した。MS：C₂₁H₁₆Cl₂N₂O₂Sについて(M+H)+としての実測値：431.3、433.0。 Example 184
5-Chloro-thiophene-2-carboxylic acid [3- (2'-chloro-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183. _{MS: C 21 H 16 Cl 2} N 2 O for ₂ S (M + H) + as the measured value: 431.3,433.0.

標題化合物を、実施例183に記載のものと同様の方法により調製した。MS：C₂₂H₁₉ClN₂O₂S₂について(M+H)+としての実測値：429.0、431.0。 Example 185
5-Chloro-thiophene-2-carboxylic acid [3- (2'-methylsulfanyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183. _{MS: C 22 H 19 ClN 2} O 2 for S ₂ (M + H) + as the measured value: 429.0,431.0.

標題化合物を、実施例183に記載のものと同様の方法により調製した。MS：C₂₁H₁₈ClN₃O₂Sについて(M+H)+としての実測値：412.3、414.3。 Example 186
5-Chloro-thiophene-2-carboxylic acid [3- (2'-amino-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183. _{MS: C 21 H 18 ClN 3} O 2 for S (M + H) + as the measured value: 412.3,414.3.

標題化合物を、実施例183に記載のものと同様の方法により調製した。MS：C₂₂H₁₆ClF₃N₂O₂Sについて(M+H)+としての実測値：465.5、467.5。 Example 187
5-Chloro-thiophene-2-carboxylic acid [3- (2'-trifluoromethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183. _{MS: C 22 H 16 ClF 3} N 2 O for ₂ S (M + H) + as the measured value: 465.5,467.5.

標題化合物を、実施例183に記載のものと同様の方法により調製した。MS：C₂₂H₁₉ClN₂O₃Sについて(M+H)+としての実測値：505.4、507.4。 Example 188
5-Chloro-thiophene-2-carboxylic acid [3- (2'-methoxy-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183. _{MS: C 22 H 19 ClN 2} O 3 for S (M + H) + as the measured value: 505.4,507.4.

標題化合物を、実施例183に記載のものと同様の方法により調製した。MS：C₂₃H₁₉ClN₂O₃Sについて(M+H)+としての実測値：519.4、521.4。 Example 189
5-Chloro-thiophene-2-carboxylic acid [3- (2'-methoxymethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183. _{MS: C 23 H 19 ClN 2} O 3 for S (M + H) + as the measured value: 519.4,521.4.

標題化合物を、実施例183に記載のものと同様の方法により調製した。MS：C₂₀H₁₆ClN₃O₂Sについて(M+H)⁺としての実測値：398.4、400.4。 Example 190
5-Chloro-thiophene-2-carboxylic acid [3- (4-pyridin-3-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183. _{MS: C 20 H 16 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 398.4,400.4.

標題化合物を、実施例183に記載のものと同様の方法により調製した。MS：C₂₀H₁₆ClN₃O₂Sについて(M+H)⁺としての実測値：398.4、400.4。 Example 191
5-Chloro-thiophene-2-carboxylic acid [3- (4-pyridin-4-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183. _{MS: C 20 H 16 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 398.4,400.4.

標題化合物を、実施例183に記載のものと同様の方法により調製した。MS：C₂₀H₁₄ClN₃O₂Sについて(M+H)⁺としての実測値：396.4、398.4。 Example 192
5-Chloro-thiophene-2-carboxylic acid [3- (4-pyridin-3-yl-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183. _{MS: C 20 H 14 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 396.4,398.4.

標題化合物を、実施例183に記載のものと同様の方法により調製した。MS：C₂₀H₁₄ClN₃O₂Sについて(M+H)⁺としての実測値：396.4、398.4。 Example 193
5-Chloro-thiophene-2-carboxylic acid [3- (4-pyridin-4-yl-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183. _{MS: C 20 H 14 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 396.4,398.4.

標題化合物を、実施例169、段階7に記載のものと同様の方法により、出発原料として実施例183からの材料を用いて調製した。MS：C₂₄H₂₄ClN₃O₂Sについて(M+H)⁺としての実測値：454.0、456.0。 Example 194
5-Chloro-thiophene-2-carboxylic acid [3- (2'-dimethylaminomethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 169, Step 7, using the material from Example 183 as the starting material. _{MS: C 24 H 24 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 454.0,456.0.

標題化合物を、実施例194に記載のものと同様の方法により調製した。MS：C₂₆H₂₆ClN₃O₂Sについて(M+H)+としての実測値：481.2、482.2。 Example 195
5-Chloro-thiophene-2-carboxylic acid [3- (2'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 194. _{MS: C 26 H 26 ClN 3} O 2 for S (M + H) + as the measured value: 481.2,482.2.

標題化合物を、実施例194に記載のものと同様の方法により調製した。MS：C₂₇H₂₈ClN₃O₂Sについて(M+H)+としての実測値：494.3、496.3。 Example 196
5-Chloro-thiophene-2-carboxylic acid [3- (2'-piperidin-1-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 194. _{MS: C 27 H 28 ClN 3} O 2 for S (M + H) + as the measured value: 494.3,496.3.

標題化合物を、実施例194に記載のものと同様の方法により調製した。MS：C₂₆H₂₆ClN₃O₃Sについて(M+H)+としての実測値：496.3、498.3。 Example 197
5-Chloro-thiophene-2-carboxylic acid [3- (2'-morpholin-4-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 194. _{MS: C 26 H 26 ClN 3} O 3 for S (M + H) + as the measured value: 496.3,498.3.

標題化合物を、実施例194に記載のものと同様の方法により調製した。MS：C₂₆H₂₈ClN₃O₃Sについて(M+H)+としての実測値：498.3、500.3。 Example 198
5-chloro-thiophene-2-carboxylic acid [3- (2 '-{[(2-methoxy-ethyl) -methyl-amino] -methyl} -biphenyl-4-yl) -4,5-dihydro-isoxazole- 5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 194. _{MS: C 26 H 28 ClN 3} O 3 for S (M + H) + as the measured value: 498.3,500.3.

標題化合物を、実施例194に記載のものと同様の方法により調製した。MS：C₂₇H₂₉ClN₄O₂Sについて(M+H)+としての実測値：509.7、511.7。 Example 199
5-chloro-thiophene-2-carboxylic acid {3- [2 '-(4-methyl-piperazin-1-ylmethyl) -biphenyl-4-yl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 194. _{MS: C 27 H 29 ClN 4} O 2 for S (M + H) + as the measured value: 509.7,511.7.

標題化合物を、実施例194に記載のものと同様の方法により調製した。MS：C₂₇H₃₁ClN₄O₂Sについて(M+H)+としての実測値：511.3、513.3。 Example 200
5-Chloro-thiophene-2-carboxylic acid [3- (2 '-{[(2-dimethylamino-ethyl) -methyl-amino] -methyl} -biphenyl-4-yl) -4,5-dihydro-isoxazole -5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 194. _{MS: C 27 H 31 ClN 4} O 2 for S (M + H) + as the measured value: 511.3,513.3.

標題化合物を、実施例194に記載のものと同様の方法により調製した。MS：C₂₈H₃₀ClN₃O₂Sについて(M+H)+としての実測値：508.3、510.4。 Example 201
5-Chloro-thiophene-2-carboxylic acid [3- (2'-azepan-1-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 194. _{MS: C 28 H 30 ClN 3} O 2 for S (M + H) + as the measured value: 508.3,510.4.

標題化合物を、実施例194に記載のものと同様の方法により調製した。MS：C₂₅H₂₆ClN₃O₃Sについて(M+H)⁺としての実測値：484.1、486.1。 Example 202
5-Chloro-thiophene-2-carboxylic acid [3- (2'-dimethylaminomethyl-5'-methoxy-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 194. _{MS: C 25 H 26 ClN 3} O 3 for S (M ⁺ H) + as the measured value: 484.1,486.1.

標題化合物を、実施例194に記載のものと同様の方法により調製した。MS：C₂₇H₂₈ClN₃O₃Sについて(M+H)⁺としての実測値：510.1、512.1。 Example 203
5-Chloro-thiophene-2-carboxylic acid [3- (5'-methoxy-2'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 194. _{MS: C 27 H 28 ClN 3} O 3 for S (M ⁺ H) + as the measured value: 510.1,512.1.

標題化合物を、実施例194に記載のものと同様の方法により調製した。MS：C₂₄H₂₃Cl₂N₃O₂Sについて(M+H)+としての実測値：488.3、490.3。 Example 204
5-Chloro-thiophene-2-carboxylic acid [3- (5'-chloro-2'-dimethylaminomethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 194. _{MS: C 24 H 23 Cl 2} N 3 O for ₂ S (M + H) + as the measured value: 488.3,490.3.

標題化合物を、実施例194に記載のものと同様の方法により調製した。MS：C₂₆H₂₅Cl₂N₃O₂Sについて(M+H)+としての実測値：514.3、516.3。 Example 205
5-Chloro-thiophene-2-carboxylic acid [3- (5'-chloro-2'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 194. _{MS: C 26 H 25 Cl 2} N 3 O 2 S for (M + H) + as the measured value: 514.3,516.3.

標題化合物を、実施例194に記載のものと同様の方法により調製した。MS：C₂₆H₂₇Cl₂N₃O₃Sについて(M+H)+としての実測値：532.4、534.4。 Example 206
5-chloro-thiophene-2-carboxylic acid [3- (5'-chloro-2 '-{[(2-methoxy-ethyl) -methyl-amino] -methyl} -biphenyl-4-yl) -4,5 -Dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 194. MS: C ₂₆ H ₂₇ Cl for _{2 N 3 O 3 S (M} + H) + as the measured value: 532.4,534.4.

標題化合物を、実施例183に記載のものと同様の方法により調製した。MS：C₂₃H₂₁ClN₂O₄Sについて(M+H)+としての実測値：457.5、459.5。 Example 207
5-Chloro-thiophene-2-carboxylic acid [3- (2'-hydroxymethyl-4'-methoxy-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183. _{MS: C 23 H 21 ClN 2} O 4 for S (M + H) + as the measured value: 457.5,459.5.

標題化合物を、実施例183に記載のものと同様の方法により調製した。MS：C₂₂H₁₅ClN₂O₃Sについて(M+H)⁺としての実測値：423.4、425.4。 Example 208
5-Chloro-thiophene-2-carboxylic acid [3- (2'-formyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183. _{MS: C 22 H 15 ClN 2} O 3 for S (M ⁺ H) + as the measured value: 423.4,425.4.

標題化合物を、実施例169に記載のものと同様の方法により、実施例208からの材料を用いて調製した。MS：C₂₄H₂₂ClN₃O₂Sについて(M+H)⁺としての実測値：452.1、454.1。 Example 209
5-Chloro-thiophene-2-carboxylic acid [3- (2'-dimethylaminomethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared using the material from Example 208 by a method similar to that described in Example 169. _{MS: C 24 H 22 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 452.1,454.1.

標題化合物を、実施例209に記載のものと同様の方法により調製した。MS：C₂₆H₂₄ClN₃O₂Sについて(M+H)⁺としての実測値：478.1、480.1。 Example 210
5-Chloro-thiophene-2-carboxylic acid [3- (2'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 209. _{MS: C 26 H 24 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 478.1,480.1.

標題化合物を、実施例209に記載のものと同様の方法により調製した。MS：C₂₄H₂₂ClN₃O₂Sについて(M+H)⁺としての実測値：452.5、454.5。 Example 211
5-Chloro-thiophene-2-carboxylic acid [3- (3'-dimethylaminomethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 209. _{MS: C 24 H 22 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 452.5,454.5.

標題化合物を、実施例209に記載のものと同様の方法により調製した。MS：C₂₆H₂₄ClN₃O₂Sについて(M+H)⁺としての実測値：478.5、480.5。 Example 212
5-Chloro-thiophene-2-carboxylic acid [3- (3'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 209. _{MS: C 26 H 24 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 478.5,480.5.

標題化合物を、実施例209に記載のものと同様の方法により調製した。MS：C₂₄H₂₂ClN₃O₂Sについて(M+H)⁺としての実測値：452.5、454.5。 Example 213
5-Chloro-thiophene-2-carboxylic acid [3- (4'-dimethylaminomethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 209. _{MS: C 24 H 22 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 452.5,454.5.

標題化合物を、実施例209に記載のものと同様の方法により調製した。MS：C₂₆H₂₄ClN₃O₂Sについて(M+H)⁺としての実測値：478.5、480.5。 Example 214
5-Chloro-thiophene-2-carboxylic acid [3- (4'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 209. _{MS: C 26 H 24 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 478.5,480.5.

標題化合物を、実施例209に記載のものと同様の方法により調製した。MS：C₂₅H₂₄ClN₃O₃Sについて(M+H)⁺としての実測値：482.1、484.1。 Example 215
5-Chloro-thiophene-2-carboxylic acid [3- (2'-dimethylaminomethyl-5'-methoxy-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 209. _{MS: C 25 H 24 ClN 3} O 3 for S (M ⁺ H) + as the measured value: 482.1,484.1.

標題化合物を、実施例209に記載のものと同様の方法により調製した。MS：C₂₇H₂₆ClN₃O₃Sについて(M+H)⁺としての実測値：508.1、510.1。 Example 216
5-Chloro-thiophene-2-carboxylic acid [3- (5'-methoxy-2'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 209. _{MS: C 27 H 26 ClN 3} O 3 for S (M ⁺ H) + as the measured value: 508.1,510.1.

標題化合物を、実施例209に記載のものと同様の方法により調製した。MS：C₂₅H₂₄ClN₃O₃Sについて(M+H)+としての実測値 Example 217
5-Chloro-thiophene-2-carboxylic acid [3- (2'-dimethylaminomethyl-4'-methoxy-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 209. MS: Measured value as (M + H) + for C ₂₅ H ₂₄ ClN ₃ O ₃ S

標題化合物を、実施例209に記載のものと同様の方法により調製した。MS：C₂₇H₂₆ClN₃O₃Sについて(M+H)+としての実測値 Example 218
5-Chloro-thiophene-2-carboxylic acid [3- (4'-methoxy-2'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 209. MS: C ₂₇ H ₂₆ ClN ₃ O ₃ S measured as (M + H) +

実施例からの臭化物1(50mg、0.13mmol)を2-ピリジルトリブチルスタンナン(55mg、0.15mmol)および5mLのトルエンと混合した。混合物を3分間脱気し、次いでテトラキストリフェニルホスフィンパラジウム(14mg、0.013mmol)で処理し、還流点で終夜撹拌した。翌日、反応をTLCでチェックし、出発原料臭化物の消費と、極性の高いスポットが確認された。反応混合物をアリールナトリウム水溶液および酢酸エチルで分配し、分離し、硫酸マグネシウムで乾燥した。ろ過し、濃縮した後、粗製残渣を調製用HPLCで精製して、所望の生成物を白色固体で得た。MS：C₂₀H₁₆ClN₃O₂Sについて(M+H)⁺としての実測値：398.1、400.1。 Example 219
5-Chloro-thiophene-2-carboxylic acid [3- (4-pyridin-2-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

Bromide 1 from the example (50 mg, 0.13 mmol) was mixed with 2-pyridyltributylstannane (55 mg, 0.15 mmol) and 5 mL of toluene. The mixture was degassed for 3 minutes and then treated with tetrakistriphenylphosphine palladium (14 mg, 0.013 mmol) and stirred at reflux overnight. The next day, the reaction was checked by TLC, confirming consumption of starting bromide and highly polar spots. The reaction mixture was partitioned between aqueous aryl sodium and ethyl acetate, separated and dried over magnesium sulfate. After filtration and concentration, the crude residue was purified by preparative HPLC to give the desired product as a white solid. _{MS: C 20 H 16 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 398.1,400.1.

標題化合物を、実施例219に記載のものと同様の方法により調製した。MS：C₂₀H₁₄ClN₃O₂Sについて(M+H)⁺としての実測値：396.1、398.1。 Example 220
5-Chloro-thiophene-2-carboxylic acid [3- (4-pyridin-2-yl-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 219. _{MS: C 20 H 14 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 396.1,398.1.

標題化合物を、実施例169、段階7に記載のものと同様の方法により調製した。MS：C₂₂H₂₀ClN₃O₂Sについて(M+H)+としての実測値：426.1、428.1。 Example 221
5-Chloro-thiophene-2-carboxylic acid [3- (4-benzylamino-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 169, Step 7. _{MS: C 22 H 20 ClN 3} O 2 for S (M + H) + as the measured value: 426.1,428.1.

臭化アリール(実施例1、100mg、0.25mmol)、アニリン(27uL、0.30mmol)、Cs₂CO₃(163mg、0.50mmol)およびXantphos(43mg、0.075mmol)を4mLの脱気THFで希釈した。得られた懸濁液をさらに3分間脱気し、次いでPd₂(dba)₃(23mg、0.25mmol)を加えると暗紫色懸濁液となり、これは数分以内に濃い黄橙色となった。次いで、混合物を終夜還流し、臭化アリールが消費されるにつれて混濁した橙色に変化した。翌日、混合物を水および酢酸エチルで分配し、分離し、有機層を酢酸エチルで抽出した。合わせた有機層をMgSO₄で乾燥し、ろ過し、濃縮し、調製用HPLCで精製して、所望の生成物を白色粉末で得た。MS：C₂₁H₁₈ClN₃O₂Sについて(M+H)⁺としての実測値：412.0、414.0。 Example 222
5-Chloro-thiophene-2-carboxylic acid [3- (4-phenylamino-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

Aryl bromide (Example 1, 100 mg, 0.25 mmol), aniline (27 uL, 0.30 mmol), Cs ₂ CO ₃ (163 mg, 0.50 mmol) and Xantphos (43 mg, 0.075 mmol) were diluted with 4 mL of degassed THF. The resulting suspension was degassed for an additional 3 minutes and then Pd ₂ (dba) ₃ (23 mg, 0.25 mmol) was added to give a dark purple suspension that became a deep yellow-orange within a few minutes. The mixture was then refluxed overnight and turned turbid orange as the aryl bromide was consumed. The next day, the mixture was partitioned with water and ethyl acetate, separated and the organic layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO ₄ , filtered, concentrated and purified by preparative HPLC to give the desired product as a white powder. _{MS: C 21 H 18 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 412.0,414.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₁H₁₇ClFN₃O₂Sについて(M+H)+としての実測値：430.1、433.1。 Example 223
5-chloro-thiophene-2-carboxylic acid {3- [4- (4-fluoro-phenylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 21 H 17 ClFN 3} O 2 for S (M + H) + as the measured value: 430.1,433.1.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₁₇ClN₄O₂Sについて(M+H)⁺としての実測値：413.0、415.0。 Example 224
5-Chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-2-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 20 H 17 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 413.0,415.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。C₂₀H₁₇ClN₄O₂Sについて(M+H)⁺としての実測値：413.0、415.0。 Example 225
5-Chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-3-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. C ₂₀ H ₁₇ ClN ₄ O ₂ S found as (M + H) ⁺ : 413.0, 415.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。C₂₀H₁₇ClN₄O₂Sについて(M+H)⁺としての実測値：413.0、415.0。 Example 226
5-Chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. C ₂₀ H ₁₇ ClN ₄ O ₂ S found as (M + H) ⁺ : 413.0, 415.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₁H₁₉ClN₄O₂Sについて(M+H)+としての実測値：427.4、429.4。 Example 227
5-Chloro-thiophene-2-carboxylic acid {3- [4- (methyl-pyridin-4-yl-amino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 21 H 19 ClN 4} O 2 for S (M + H) + as the measured value: 427.4,429.4.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₁H₁₉ClN₄O₂Sについて(M+H)+としての実測値：427.1、429.1。 Example 228
5-chloro-thiophene-2-carboxylic acid {3- [4- (2-methyl-pyridin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 21 H 19 ClN 4} O 2 for S (M + H) + as the measured value: 427.1,429.1.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₁₆Cl₂N4O₂Sについて(M+H)+としての実測値：447.2、449.2。 Example 229
5-chloro-thiophene-2-carboxylic acid {3- [4- (2-chloro-pyridin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 20 H 16 Cl 2} N4O for ₂ S (M + H) + as the measured value: 447.2,449.2.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₁₉H₁₆ClN₅O₂Sについて(M+H)+としての実測値：414.1、416.1、(M+Na)⁺としての実測値：436.0、438.0 Example 230
5-Chloro-thiophene-2-carboxylic acid {3- [4- (pyrimidin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. MS: C ₁₉ H ₁₆ ClN ₅ O ₂ S measured values as (M + H) +: 414.1, 416.1, measured values as (M + Na) ⁺ : 436.0, 438.0

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClN₆O₂Sについて(M+H)⁺としての実測値：433.3、435.3。 Example 231
5-Chloro-thiophene-2-carboxylic acid (3- {4-[(2-amino-pyrimidin-4-yl) -methyl-amino] -phenyl} -4,5-dihydro-isoxazol-5-ylmethyl)- Amide

The title compound was prepared in a similar manner as described in Example 222. MS: C ₂₀ H ₁₉ ClN about _{6 O 2 S (M + H} ) + as the measured value: 433.3,435.3.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₂₀ClN₅O₂Sについて(M+H)⁺としての実測値：430.2、432.3。 Example 232
5-chloro-thiophene-2-carboxylic acid {3- [4- (2-ethyl-2H-pyrazol-3-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl-amide

The title compound was prepared in a similar manner as described in Example 222. MS: C ₂₀ H ₂₀ ClN about _{5 O 2 S (M + H} ) + as the measured value: 430.2,432.3.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₁₉H₁₈ClN₅O₂Sについて(M+H)+としての実測値：416.5、418.5。 Example 233
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-1H-pyrazol-3-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. MS: C ₁₉ H ₁₈ ClN about _{5 O 2 S (M + H} ) + as the measured value: 416.5,418.5.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₁₉H₂₀ClN₃O₃Sについて(M+H)⁺としての実測値：406.3、408.3；(M+Na)⁺としての実測値：428.2、430.2。 Example 234
5-Chloro-thiophene-2-carboxylic acid [3- (4-morpholin-4-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 19 H 20 ClN 3} O 3 for S (M ⁺ H) + as the measured value: 406.3,408.3; (M + Na) + as the measured value: 428.2,430.2.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₂₃ClN₄O₂Sについて(M+H)⁺としての実測値：419.3、421.3。 Example 235
5-chloro-thiophene-2-carboxylic acid {3- [4- (4-methyl-piperazin-1-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 20 H 23 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 419.3,421.3.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₁H₂₄ClN₃O₃Sについて(M+H)⁺としての実測値：434.0、436.0。 Example 236
5-Chloro-thiophene-2-carboxylic acid {3- [4- (2-methoxymethyl-pyrrolidin-1-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 21 H 24 ClN 3} O 3 for S (M ⁺ H) + as the measured value: 434.0,436.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₁H₂₅ClN₄O₂Sについて(M+H)⁺としての実測値：433.3、435.3。 Example 237
5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-piperidin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 21 H 25 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 433.3,435.3.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₂₅ClN₄O₂Sについて(M+H)+としての実測値：421.3、423.3。 Example 238
5-Chloro-thiophene-2-carboxylic acid (3- {4-[(2-dimethylamino-ethyl) -methyl-amino] -phenyl} -4,5-dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 20 H 25 ClN 4} O 2 for S (M + H) + as the measured value: 421.3,423.3.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₁H₂₇ClN₄O₂Sについて(M+H)⁺としての実測値：421.0、423.0。 Example 239
5-Chloro-thiophene-2-carboxylic acid (3- {4-[(3-dimethylamino-propyl) -methyl-amino] -phenyl} -4,5-dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 21 H 27 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 421.0,423.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₁₉H₁₈ClN₃O₃Sについて(M+H)⁺としての実測値：404.2、406.2。 Example 240
5-Chloro-thiophene-2-carboxylic acid {3- [4- (2-oxo-pyrrolidin-1-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 19 H 18 ClN 3} O 3 for S (M ⁺ H) + as the measured value: 404.2,406.2.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₂₀ClN₃O₃Sについて(M+H)⁺としての実測値：418.2、420.2。 Example 241
5-chloro-thiophene-2-carboxylic acid {3- [4- (2-oxo-piperidin-1-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 20 H 20 ClN 3} O 3 for S (M ⁺ H) + as the measured value: 418.2,420.2.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₇H₂₅ClN₄O₅Sについて(M+H)⁺としての実測値：553.3、555.3。 Example 242
4- [4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenyl] -3-oxo-piperazine- 1-carboxylic acid benzyl ester

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 27 H 25 ClN 4} O 5 for S (M ⁺ H) + as the measured value: 553.3,555.3.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₁₉H₁₈ClN₃O₄Sについて(M-H)⁺としての実測値：418.1、420.1。 Example 243
5-Chloro-thiophene-2-carboxylic acid {3- [4- (3-oxo-morpholin-4-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 19 H 18 ClN 3} O 4 for S (MH) ⁺ as the Found: 418.1,420.1.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₁₉H₁₈ClN₃O₃S₂について(M+H)⁺としての実測値：436.2、438.2。 Example 244
5-Chloro-thiophene-2-carboxylic acid {3- [4- (3-oxo-thiomorpholin-4-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. MS: C ₁₉ H ₁₈ For _{ClN 3 O 3 S 2 (M} + H) + as the measured value: 436.2,438.2.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₁₉H₁₉ClN₄O₃Sについて(M+H)⁺としての実測値：419.2、421.2。 Example 245
5-chloro-thiophene-2-carboxylic acid {3- [4- (3-methyl-2-oxo-imidazolidin-1-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 19 H 19 ClN 4} O 3 for S (M ⁺ H) + as the measured value: 419.2,421.2.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₂₀ClN₃O₄Sについて(M+H)⁺としての実測値：434.5、436.5。 Example 246
5-Chloro-thiophene-2-carboxylic acid {3- [4- (5-oxo- [1,4] oxazepan-4-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 20 H 20 ClN 3} O 4 for S (M ⁺ H) + as the measured value: 434.5,436.5.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₁₆ClFN₄O₂Sについて(M+H)⁺としての実測値：431.1、433.1。 Example 247
5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (pyridin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl) -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 20 H 16 ClFN 4} O 2 for S (M ⁺ H) + as the measured value: 431.1,433.1.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₁H₂₄ClFN₄O₂Sについて(M+H)⁺としての実測値：451.2、453.3。 Example 248
5-Chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (4-methyl- [1,4] diazepan-1-yl) -phenyl] -4,5-dihydro-isoxazole-5- Ilmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 21 H 24 ClFN 4} O 2 for S (M ⁺ H) + as the measured value: 451.2,453.3.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClFN₃O₄Sについて(M+H)⁺としての実測値：452.0、454.0。 Example 249
5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (5-oxo- [1,4] oxazepan-4-yl) -phenyl] -4,5-dihydro-isoxazol-5- Ilmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 20 H 19 ClFN 3} O 4 for S (M ⁺ H) + as the measured value: 452.0,454.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₁H₁₆ClN₃O₂Sについて(M+H)+としての実測値：410.4、412.3。 Example 250
5-Chloro-thiophene-2-carboxylic acid [3- (4-phenylamino-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 21 H 16 ClN 3} O 2 for S (M + H) + as the measured value: 410.4,412.3.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₂H₁₈ClN₃O₃Sについて(M+H)⁺としての実測値：440.0、442.0。 Example 251
5-Chloro-thiophene-2-carboxylic acid {3- [4- (4-methoxy-phenylamino) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 22 H 18 ClN 3} O 3 for S (M ⁺ H) + as the measured value: 440.0,442.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₁₅ClN₄O₂Sについて(M+H)⁺としての実測値：411.0、413.0。 Example 252
5-Chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-2-ylamino) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 20 H 15 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 411.0,413.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₁₅ClN₄O₂Sについて(M+H)⁺としての実測値：411.0、413.1。 Example 253
5-Chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-3-ylamino) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 20 H 15 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 411.0,413.1.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₁₅ClN₄O₂Sについて(M+H)⁺としての実測値：411.0、413.0。 Example 254
5-Chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-4-ylamino) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 20 H 15 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 411.0,413.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₁H₁₇ClN₄O₂Sについて(M+H)+としての実測値：425.0、427.0。 Example 255
5-Chloro-thiophene-2-carboxylic acid {3- [4- (methyl-pyridin-4-yl-amino) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 21 H 17 ClN 4} O 2 for S (M + H) + as the measured value: 425.0,427.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₁₉H₁₈ClN₃O₂Sについて(M+H)+としての実測値：388.4、390.4。 Example 256
5-Chloro-thiophene-2-carboxylic acid [3- (4-pyrrolidin-1-yl-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 19 H 18 ClN 3} O 2 for S (M + H) + as the measured value: 388.4,390.4.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₁₉H₁₈ClN₃O₃Sについて(M+H)⁺としての実測値：404.3、406.3。 Example 257
5-Chloro-thiophene-2-carboxylic acid [3- (4-morpholin-4-yl-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 19 H 18 ClN 3} O 3 for S (M ⁺ H) + as the measured value: 404.3,406.3.

標題化合物を、実施例169、段階7に記載のものと同様の方法により調製した。MS：C₂₂H₁₈ClN₃O₂Sについて(M+H)+としての実測値：424.0、426.0。 Example 258
5-Chloro-thiophene-2-carboxylic acid [3- (4-benzylamino-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 169, Step 7. _{MS: C 22 H 18 ClN 3} O 2 for S (M + H) + as the measured value: 424.0,426.0.

標題化合物を、実施例169、段階7に記載のものと同様の方法により調製した。MS：C₂₁H₂₃ClN₄O₂Sについて(M+H)⁺としての実測値：431.4、433.4。 Example 259
5-Chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-piperidin-4-ylamino) -phenyl] -isoxazol-5-ylmethyl} -amide

The title compound was prepared by a method similar to that described in Example 169, Step 7. _{MS: C 21 H 23 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 431.4,433.4.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₃H₂₀ClN₃O₄Sについて(M+H)⁺としての実測値：470.0、472.0。 Example 260
2- [4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenylamino] -benzoic acid methyl ester

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 23 H 20 ClN 3} O 4 for S (M ⁺ H) + as the measured value: 470.0,472.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₃H₂₀ClN₃O₄Sについて(M+H)⁺としての実測値：470.0、472.0。 Example 261
3- [4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenylamino] -benzoic acid methyl ester

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 23 H 20 ClN 3} O 4 for S (M ⁺ H) + as the measured value: 470.0,472.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₃H₂₀ClN₃O₄Sについて(M+H)⁺としての実測値：470.0、472.0。 Example 262
4- [4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenylamino] -benzoic acid methyl ester

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 23 H 20 ClN 3} O 4 for S (M ⁺ H) + as the measured value: 470.0,472.0.

標題化合物を、実施例3からの出発原料臭化物を用いて実施例183に記載のものと同様の方法により、続いて実施例169、段階7の方法により調製した。MS：C₂₆H₂₆ClN₃O₂Sについて(M+H)⁺としての実測値：480.5、482.5。 Example 263
5-Chloro-thiophene-2-carboxylic acid [3- (2'-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183 using the starting bromide from Example 3, followed by the method of Example 169, Step 7. _{MS: C 26 H 26 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 480.5,482.5.

標題化合物を、実施例3からの出発原料臭化物を用いて実施例183に記載のものと同様の方法により、続いて実施例169、段階7の方法により調製した。MS：C₂₄H₂₄ClN₃O₂Sについて(M+H)⁺としての実測値：454.1、456.1。 Example 264
5-Chloro-thiophene-2-carboxylic acid [3- (3'-dimethylaminomethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183 using the starting bromide from Example 3, followed by the method of Example 169, Step 7. _{MS: C 24 H 24 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 454.1,456.1.

標題化合物を、実施例3からの出発原料臭化物を用いて実施例183に記載のものと同様の方法により、続いて実施例169、段階7の方法により調製した。MS：C₂₆H₂₆ClN₃O₂Sについて(M+H)⁺としての実測値：480.1、482.1。 Example 265
5-Chloro-thiophene-2-carboxylic acid [3- (3'-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183 using the starting bromide from Example 3, followed by the method of Example 169, Step 7. _{MS: C 26 H 26 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 480.1,482.1.

標題化合物を、実施例3からの出発原料臭化物を用いて実施例183に記載のものと同様の方法により、続いて実施例169、段階7の方法により調製した。MS：C₂₄H₂₄ClN₃O₂Sについて(M+H)⁺としての実測値：454.1、456.1。 Example 266
5-Chloro-thiophene-2-carboxylic acid [3- (4'-dimethylaminomethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183 using the starting bromide from Example 3, followed by the method of Example 169, Step 7. _{MS: C 24 H 24 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 454.1,456.1.

標題化合物を、実施例3からの出発原料臭化物を用いて実施例183に記載のものと同様の方法により、続いて実施例169、段階7の方法により調製した。MS：C₂₆H₂₆ClN₃O₂Sについて(M+H)⁺としての実測値：480.1、482.1。 Example 267
5-Chloro-thiophene-2-carboxylic acid [3- (4'-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183 using the starting bromide from Example 3, followed by the method of Example 169, Step 7. _{MS: C 26 H 26 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 480.1,482.1.

標題化合物を、実施例4からの出発原料臭化物を用いて実施例183に記載のものと同様の方法により、続いて実施例169、段階7の方法により調製した。MS：C₂₄H₂₂ClN₃O₂Sについて(M+H)⁺としての実測値：452.5、454.5。 Example 268
5-Chloro-thiophene-2-carboxylic acid [3- (2'-dimethylaminomethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183 using the starting bromide from Example 4, followed by the method of Example 169, Step 7. _{MS: C 24 H 22 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 452.5,454.5.

標題化合物を、実施例4からの出発原料臭化物を用いて実施例183に記載のものと同様の方法により、続いて実施例169、段階7の方法により調製した。MS：C₂₆H₂₄ClN₃O₂Sについて(M+H)⁺としての実測値：478.5、480.5。 Example 269
5-Chloro-thiophene-2-carboxylic acid [3- (2'-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183 using the starting bromide from Example 4, followed by the method of Example 169, Step 7. _{MS: C 26 H 24 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 478.5,480.5.

標題化合物を、実施例4からの出発原料臭化物を用いて実施例183に記載のものと同様の方法により、続いて実施例169、段階7の方法により調製した。MS：C₂₄H₂₂ClN₃O₂Sについて(M+H)+としての実測値：452.1、454.1。 Example 270
5-Chloro-thiophene-2-carboxylic acid [3- (3'-dimethylaminomethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183 using the starting bromide from Example 4, followed by the method of Example 169, Step 7. _{MS: C 24 H 22 ClN 3} O 2 for S (M + H) + as the measured value: 452.1,454.1.

標題化合物を、実施例4からの出発原料臭化物を用いて実施例183に記載のものと同様の方法により、続いて実施例169、段階7の方法により調製した。MS：C₂₆H₂₄ClN₃O₂Sについて(M+H)⁺としての実測値：478.1、480.1。 Example 271
5-Chloro-thiophene-2-carboxylic acid [3- (3'-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183 using the starting bromide from Example 4, followed by the method of Example 169, Step 7. _{MS: C 26 H 24 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 478.1,480.1.

標題化合物を、実施例4からの出発原料臭化物を用いて実施例183に記載のものと同様の方法により、続いて実施例169、段階7の方法により調製した。MS：C₂₄H₂₂ClN₃O₂Sについて(M+H)+としての実測値：452.1、454.1。 Example 272
5-Chloro-thiophene-2-carboxylic acid [3- (4'-dimethylaminomethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183 using the starting bromide from Example 4, followed by the method of Example 169, Step 7. _{MS: C 24 H 22 ClN 3} O 2 for S (M + H) + as the measured value: 452.1,454.1.

標題化合物を、実施例4からの出発原料臭化物を用いて実施例183に記載のものと同様の方法により、続いて実施例169、段階7の方法により調製した。MS：C₂₆H₂₄ClN₃O₂Sについて(M+H)⁺としての実測値：478.1、480.1。 Example 273
5-Chloro-thiophene-2-carboxylic acid [3- (4'-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183 using the starting bromide from Example 4, followed by the method of Example 169, Step 7. _{MS: C 26 H 24 ClN 3} O 2 for S (M ⁺ H) + as the measured value: 478.1,480.1.

標題化合物を、実施例183に記載のものと同様の方法により調製した。

Example 274
5-Chloro-thiophene-2-carboxylic acid [3- (3-pyridin-3-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183.

標題化合物を、実施例183に記載のものと同様の方法により調製した。

Example 275
5-Chloro-thiophene-2-carboxylic acid [3- (3-pyridin-4-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183.

標題化合物を、実施例183に記載のものと同様の方法により調製した。

Example 276
5-Chloro-thiophene-2-carboxylic acid [3- (3-pyridin-3-yl-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183.

標題化合物を、実施例183に記載のものと同様の方法により調製した。

Example 277
5-Chloro-thiophene-2-carboxylic acid [3- (3-pyridin-4-yl-phenyl) -isoxazol-5-ylmethyl] -amide

The title compound was prepared by a method similar to that described in Example 183.

臭化アリール(実施例1、100mg、0.25mmol)および2-ヒドロキシピリジン(95mg、1.0mmol)を1.5mLの無水ジオキサンおよび0.5mLの無水DMSOに密封試験管中で溶解した。これにN,N'-ジメチルエチレンジアミン(27μL、0.25mmol)、CuI(95mg、0.125mmol)およびK₃PO₄(106mg、0.5mmol)を順に加えた。混合物を120℃の浴中で臭化物出発原料がすべて消費されるまで(3時間、分析用HPLCでモニターした)撹拌加熱した。混合物をろ過し、調製用逆相HPLCに直接かけ、凍結乾燥後に標題化合物を白色粉末で単離した。MS：C₂₀H₁₆ClN₃O₃Sについて(M+H)+としての実測値：414.1、416.1。 Example 278
5-Chloro-N-((3- (4- (2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide

Aryl bromide (Example 1, 100 mg, 0.25 mmol) and 2-hydroxypyridine (95 mg, 1.0 mmol) were dissolved in 1.5 mL anhydrous dioxane and 0.5 mL anhydrous DMSO in a sealed tube. To this, N, N′-dimethylethylenediamine (27 μL, 0.25 mmol), CuI (95 mg, 0.125 mmol) and K ₃ PO ₄ (106 mg, 0.5 mmol) were sequentially added. The mixture was stirred and heated in a 120 ° C. bath until all bromide starting material was consumed (monitored by analytical HPLC for 3 hours). The mixture was filtered and directly subjected to preparative reverse phase HPLC, and the title compound was isolated as a white powder after lyophilization. _{MS: C 20 H 16 ClN 3} O 3 for S (M + H) + as the measured value: 414.1,416.1.

標題化合物を、実施例278に記載のものと同じ方法により、2-ヒドロキシピリジンの代わりに3-フルオロ-2-ヒドロキシピリジンを用いて調製した。MS：C₂₀H₁₅ClFN₃O₃Sについて(M+H)+としての実測値：432.1、434.1。 Example 279
5-chloro-N-((3- (4- (3-fluoro-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide

The title compound was prepared by the same method as described in Example 278 using 3-fluoro-2-hydroxypyridine instead of 2-hydroxypyridine. _{MS: C 20 H 15 ClFN 3} O 3 for S (M + H) + as the measured value: 432.1,434.1.

標題化合物を、実施例278に記載のものと同じ方法により、2-ヒドロキシピリジンの代わりに5-フルオロ-2-ヒドロキシピリジンを用いて調製した。MS：C₂₀H₁₅ClFN₃O₃Sについて(M+H)+としての実測値：432.1、434.1。 Example 280
5-chloro-N-((3- (4- (5-fluoro-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene 2-carboxamide

The title compound was prepared by the same method as described in Example 278 using 5-fluoro-2-hydroxypyridine instead of 2-hydroxypyridine. _{MS: C 20 H 15 ClFN 3} O 3 for S (M + H) + as the measured value: 432.1,434.1.

標題化合物を、実施例278に記載のものと同じ方法により、2-ヒドロキシピリジンの代わりに3-メチル-2-ヒドロキシピリジンを用いて調製した。MS：C₂₁H₁₈ClN₃O₃Sについて(M+H)+としての実測値：428.1、430.1。 Example 281
5-chloro-N-((3- (4- (3-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide

The title compound was prepared by the same method as described in Example 278 using 3-methyl-2-hydroxypyridine instead of 2-hydroxypyridine. _{MS: C 21 H 18 ClN 3} O 3 for S (M + H) + as the measured value: 428.1,430.1.

標題化合物を、実施例278に記載のものと同じ方法により、2-ヒドロキシピリジンの代わりに3-メトキシ-2-ヒドロキシピリジンを用いて調製した。MS：C₂₁H₁₈ClN₃O₄Sについて(M+H)+としての実測値：444.1、446.1。 Example 282
5-chloro-N-((3- (4- (3-methoxy-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide

The title compound was prepared by the same method described in Example 278 using 3-methoxy-2-hydroxypyridine instead of 2-hydroxypyridine. _{MS: C 21 H 18 ClN 3} O 4 for S (M + H) + as the measured value: 444.1,446.1.

標題化合物を、実施例278に記載のものと同じ方法により、2-ヒドロキシピリジンの代わりに3-クロロ-2-ヒドロキシピリジンを用いて調製した。MS：C₂₀H₁₅Cl₂N₃O₃Sについて(M+H)+としての実測値：448.0、450.0。 Example 283
5-chloro-N-((3- (4- (3-chloro-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide

The title compound was prepared by the same method as described in Example 278 using 3-chloro-2-hydroxypyridine instead of 2-hydroxypyridine. MS: C ₂₀ H ₁₅ Cl for _{2 N 3 O 3 S (M} + H) + as the measured value: 448.0,450.0.

標題化合物を、実施例278に記載のものと同じ方法により、2-ヒドロキシピリジンの代わりに4-メチル-2-ヒドロキシピリジンを用いて調製した。MS：C₂₁H₁₈ClN₃O₃Sについて(M+H)+としての実測値：428.1、430.1。 Example 284
5-chloro-N-((3- (4- (4-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide

The title compound was prepared by the same method as described in Example 278 using 4-methyl-2-hydroxypyridine instead of 2-hydroxypyridine. _{MS: C 21 H 18 ClN 3} O 3 for S (M + H) + as the measured value: 428.1,430.1.

標題化合物を、実施例278に記載のものと同じ方法により、2-ヒドロキシピリジンの代わりに5-メチル-2-ヒドロキシピリジンを用いて調製した。MS：C₂₁H₁₈ClN₃O₃Sについて(M+H)+としての実測値：428.1、430.1。 Example 285
5-chloro-N-((3- (4- (5-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide

The title compound was prepared by the same method as described in Example 278 using 5-methyl-2-hydroxypyridine instead of 2-hydroxypyridine. _{MS: C 21 H 18 ClN 3} O 3 for S (M + H) + as the measured value: 428.1,430.1.

標題化合物を、実施例278に記載のものと同じ方法により、2-ヒドロキシピリジンの代わりに5-メトキシ-2-ヒドロキシピリジンを用いて調製した。MS：C₂₁H₁₈ClN₃O₄Sについて(M+H)+としての実測値：444.1、446.1。 Example 286
5-chloro-N-((3- (4- (5-methoxy-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide

The title compound was prepared by the same method as described in Example 278 using 5-methoxy-2-hydroxypyridine instead of 2-hydroxypyridine. _{MS: C 21 H 18 ClN 3} O 4 for S (M + H) + as the measured value: 444.1,446.1.

標題化合物を、実施例278に記載のものと同じ方法により、2-ヒドロキシピリジンの代わりに5-クロロ-2-ヒドロキシピリジンを用いて調製した。MS：C₂₀H₁₅Cl₂N₃O₃Sについて(M+H)+としての実測値：448.0、450.0。 Example 287
5-chloro-N-((3- (4- (5-chloro-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene- 2-carboxamide

The title compound was prepared by the same method as described in Example 278, using 5-chloro-2-hydroxypyridine instead of 2-hydroxypyridine. MS: C ₂₀ H ₁₅ Cl for _{2 N 3 O 3 S (M} + H) + as the measured value: 448.0,450.0.

標題化合物を、実施例2に記載のものと同じ方法により、4-ブロモベンズアルデヒドの代わりに4-ヨードベンズアルデヒドを用いて調製した。MS：C₁₅H₁₀ClIN₂O₂Sについて(M+H)+としての実測値：445.0、447.0。 Example 288
5-Chloro-N-((3- (4-iodophenyl) isoxazol-5-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by the same method as described in Example 2, using 4-iodobenzaldehyde instead of 4-bromobenzaldehyde. MS: C ₁₅ H ₁₀ ClIN about _{2 O 2 S (M + H} ) + as the measured value: 445.0,447.0.

ヨウ化アリール(実施例288、43mg、0.1mmol)および2-ヒドロキシピリジン(38mg、0.4mmol)を1.2mLの無水ジオキサンおよび0.5mLの無水DMSOに密封試験管中で溶解した。これにN,N'-ジメチルエチレンジアミン(11μL、0.1mmol)、CuI(10mg、0.05mmol)およびK₃PO₄(42mg、0.2mmol)を順に加えた。混合物を120℃の浴中で6時間撹拌加熱した。混合物をろ過し、調製用逆相HPLCに直接かけ、凍結乾燥後に標題化合物を白色粉末で単離した。MS：C₂₀H₁₄ClN₃O₃Sについて(M+H)+としての実測値：412.0、414.0。 Example 289
5-Chloro-N-((3- (4- (2-oxopyridin-1 (2H) -yl) phenyl) isoxazol-5-yl) methyl) thiophene-2-carboxamide

Aryl iodide (Example 288, 43 mg, 0.1 mmol) and 2-hydroxypyridine (38 mg, 0.4 mmol) were dissolved in 1.2 mL anhydrous dioxane and 0.5 mL anhydrous DMSO in a sealed tube. To this, N, N′-dimethylethylenediamine (11 μL, 0.1 mmol), CuI (10 mg, 0.05 mmol) and K ₃ PO ₄ (42 mg, 0.2 mmol) were sequentially added. The mixture was stirred and heated in a 120 ° C. bath for 6 hours. The mixture was filtered and directly subjected to preparative reverse phase HPLC, and the title compound was isolated as a white powder after lyophilization. _{MS: C 20 H 14 ClN 3} O 3 for S (M + H) + as the measured value: 412.0,414.0.

Example 290
5-Chloro-N-((1- (4- (2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide (36)
Scheme 5

Stage 1:
4-Iodoaniline (32, 6.00 g, 27.4 mmol) was dissolved in 25 mL TFA and stirred in an ice bath. Solid NaNO ₂ (2.07 g, 30.1 mmol) was added in small portions. The resulting mixture was stirred in an ice bath for 30 minutes. Sodium azide (1.87 g, 28.8 mmol) was dissolved in 10 mL water and cooled in an ice bath. This cold solution was then added to the TFA solution in three portions. The mixture was stirred in an ice bath for 1 hour and concentrated under reduced pressure to remove TFA. The residue was dissolved in 600 mL DCM and washed 3 times with water. The organic phase was dried over MgSO ₄ and concentrated in vacuo to give 1-azido-4-iodobenzene 33 as a brownish waxy solid in> 99% yield. Meanwhile, 5-chlorothiophene-2-carboxylic acid (4, 9.13 g, 56 mmol) was dissolved in 200 mL anhydrous DCM and 0.5 mL anhydrous DMF. To the vigorously stirring solution oxalyl chloride (14.7 mL, 169 mmol) was carefully added dropwise. The resulting solution was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was dried with a vacuum pump and then dissolved in 300 mL anhydrous DCM. To this solution was added propargylamine (5.8 mL, 84 mmol) dropwise. The mixture was stirred at room temperature overnight and a large amount of solid precipitated. To this mixture was added 600 mL of hexane. The mixture was stirred vigorously for several hours and the solid was filtered (product 34). The solid (9.47 g, 85%) was washed with hexane and was pure enough to be used directly without further purification. MS: for _{C 8 H 6 ClNOS (M +} H) + as the measured value: 200.0,202.0.

Stage 2:
Aryl azide 33 (27 mmol) and alkyne 34 (5.37 g, 27 mmol) were dissolved in 40 mL anhydrous DMF. To this was added 200 mL of toluene. The mixture was refluxed in a 135 ° C. bath for 1 day. The mixture was concentrated under reduced pressure and subjected to flash column chromatography to give 1,4-disubstituted triazole 35 (main product: Rf = 0.30 in hexane / EtOAc 1: 1) and its 1,5-disubstituted triazole isomer (secondary). Product: Rf = 0.17) in hexane / EtOAc 1: 1 was isolated. MS: Measured as (M + H) + for 35 C ₁₄ H ₁₀ ClN ₄ OS: 444.9, 446.9.

Stage 3:
Aryl iodide 35 (100 mg, 0.22 mmol) and 2-hydroxypyridine (42 mg, 0.44 mmol) were dissolved in 5 mL anhydrous DMSO in a sealed tube. To this was added 8-hydroxyquinoline (10 mg, 0.007 mmol), CuI (13 mg, 0.07 mmol) and Cs ₂ CO ₃ (145 mg, 0.44 mmol). The mixture was stirred in a 120 ° C. bath overnight. This was then filtered and the filtrate was subjected directly to preparative reverse phase HPLC, and the title compound 36 was isolated as a white powder after lyophilization (yield 60-75%). MS: C ₁₉ H ₁₄ ClN about _{5 O 2 S (M + H} ) + as the measured value: 412.1,414.1.

ヨウ化アリール35(実施例290、50mg、0.11mmol)および3-フルオロ-2-ヒドロキシピリジン(38mg、0.33mmol)を1.0mLの無水ジオキサンおよび0.3mLの無水DMSOに密封試験管中で溶解した。これにN,N'-ジメチルエチレンジアミン(8μL、0.066mmol)、CuI(11mg、0.055mmol)およびK₃PO₄(48mg、0.22mmol)を順に加えた。混合物を120℃の浴中で終夜撹拌加熱した。混合物をろ過し、調製用逆相HPLCに直接かけ、凍結乾燥後に標題化合物を白色粉末で単離した。MS：C₁₉H₁₃ClFN₅O₂Sについて(M+H)+としての実測値：430.0、432.0。 Example 291
5-Chloro-N-((1- (4- (3-fluoro-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide

Aryl iodide 35 (Example 290, 50 mg, 0.11 mmol) and 3-fluoro-2-hydroxypyridine (38 mg, 0.33 mmol) were dissolved in 1.0 mL anhydrous dioxane and 0.3 mL anhydrous DMSO in a sealed tube. To this, N, N′-dimethylethylenediamine (8 μL, 0.066 mmol), CuI (11 mg, 0.055 mmol) and K ₃ PO ₄ (48 mg, 0.22 mmol) were sequentially added. The mixture was stirred and heated in a 120 ° C. bath overnight. The mixture was filtered and directly subjected to preparative reverse phase HPLC, and the title compound was isolated as a white powder after lyophilization. MS: C ₁₉ H ₁₃ ClFN for _{5 O 2 S (M + H} ) + as the measured value: 430.0,432.0.

標題化合物を、実施例290に記載のものと同じ方法により、3-フルオロ-2-ヒドロキシピリジンの代わりに3-クロロ-2-ヒドロキシピリジンを用いて調製した。MS：C₁₉H₁₃Cl₂N₅O₂Sについて(M+H)+としての実測値：446.0、448.0。 Example 292
5-Chloro-N-((1- (4- (3-chloro-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide

The title compound was prepared by the same method as described in Example 290 using 3-chloro-2-hydroxypyridine instead of 3-fluoro-2-hydroxypyridine. _{MS: C 19 H 13 Cl 2} N for _{5 O 2 S (M + H} ) + as the measured value: 446.0,448.0.

標題化合物を、実施例290に記載のものと同じ方法により、3-フルオロ-2-ヒドロキシピリジンの代わりに3-メチル-2-ヒドロキシピリジンを用いて調製した。MS：C₂₀H₁₆ClN₅O₂Sについて(M+H)+としての実測値：426.1、428.1。 Example 293
5-Chloro-N-((1- (4- (3-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide

The title compound was prepared by the same method as described in Example 290 using 3-methyl-2-hydroxypyridine instead of 3-fluoro-2-hydroxypyridine. MS: C ₂₀ H ₁₆ ClN about _{5 O 2 S (M + H} ) + as the measured value: 426.1,428.1.

標題化合物を、実施例290に記載のものと同じ方法により、3-フルオロ-2-ヒドロキシピリジンの代わりに3-メトキシ-2-ヒドロキシピリジンを用いて調製した。MS：C₂₀H₁₆ClN₅O₃Sについて(M+H)+としての実測値：442.1、444.1。 Example 294
5-Chloro-N-((1- (4- (3-methoxy-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide

The title compound was prepared by the same method as described in Example 290 using 3-methoxy-2-hydroxypyridine instead of 3-fluoro-2-hydroxypyridine. _{MS: C 20 H 16 ClN 5} O 3 for S (M + H) + as the measured value: 442.1,444.1.

標題化合物を、実施例290に記載のものと同じ方法により、3-フルオロ-2-ヒドロキシピリジンの代わりに4-メチル-2-ヒドロキシピリジンを用いて調製した。MS：C₂₀H₁₆ClN₅O₂Sについて(M+H)+としての実測値：426.1、428.1。 Example 295
5-Chloro-N-((1- (4- (4-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide

The title compound was prepared by the same method as described in Example 290 using 4-methyl-2-hydroxypyridine instead of 3-fluoro-2-hydroxypyridine. MS: C ₂₀ H ₁₆ ClN about _{5 O 2 S (M + H} ) + as the measured value: 426.1,428.1.

標題化合物を、実施例290に記載のものと同じ方法により、3-フルオロ-2-ヒドロキシピリジンの代わりに5-メチル-2-ヒドロキシピリジンを用いて調製した。MS：C₂₀H₁₆ClN₅O₂Sについて(M+H)+としての実測値：426.1、428.1。 Example 296
5-chloro-N-((1- (4- (5-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide

The title compound was prepared by the same method as described in Example 290 using 5-methyl-2-hydroxypyridine instead of 3-fluoro-2-hydroxypyridine. MS: C ₂₀ H ₁₆ ClN about _{5 O 2 S (M + H} ) + as the measured value: 426.1,428.1.

標題化合物を、実施例290に記載のものと同じ方法により、3-フルオロ-2-ヒドロキシピリジンの代わりに5-メトキシ-2-ヒドロキシピリジンを用いて調製した。MS：C₂₀H₁₆ClN₅O₃Sについて(M+H)+としての実測値：442.1、444.1。 Example 297
5-Chloro-N-((1- (4- (5-methoxy-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide

The title compound was prepared by the same method as described in Example 290 using 5-methoxy-2-hydroxypyridine instead of 3-fluoro-2-hydroxypyridine. _{MS: C 20 H 16 ClN 5} O 3 for S (M + H) + as the measured value: 442.1,444.1.

標題化合物を、実施例290に記載のものと同じ方法により、3-フルオロ-2-ヒドロキシピリジンの代わりに5-フルオロ-2-ヒドロキシピリジンを用いて調製した。MS：C₁₉H₁₃ClFN₅O₂Sについて(M+H)+としての実測値：430.0、432.0。 Example 298
5-Chloro-N-((1- (4- (5-fluoro-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide

The title compound was prepared by the same method as described in Example 290 using 5-fluoro-2-hydroxypyridine instead of 3-fluoro-2-hydroxypyridine. MS: C ₁₉ H ₁₃ ClFN for _{5 O 2 S (M + H} ) + as the measured value: 430.0,432.0.

標題化合物を、実施例290に記載のものと同じ方法により、3-フルオロ-2-ヒドロキシピリジンの代わりに5-クロロ-2-ヒドロキシピリジンを用いて調製した。MS：C₁₉H₁₃Cl₂N₅O₂Sについて(M+H)+としての実測値：446.0、448.0。 Example 299
5-Chloro-N-((1- (4- (5-chloro-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide

The title compound was prepared by the same method as described in Example 290 using 5-chloro-2-hydroxypyridine instead of 3-fluoro-2-hydroxypyridine. _{MS: C 19 H 13 Cl 2} N for _{5 O 2 S (M + H} ) + as the measured value: 446.0,448.0.

標題化合物を、実施例290に記載のものと同じ方法により、3-フルオロ-2-ヒドロキシピリジンの代わりにδ-バレロラクタム(2-ピペリドン)を用いて調製した。MS：C₁₉H₁₈ClN₅O₂Sについて(M+H)+としての実測値：416.1、418.1。 Example 300
5-chloro-N-((1- (4- (2-oxopiperidin-1-yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by the same method as described in Example 290 using δ-valerolactam (2-piperidone) instead of 3-fluoro-2-hydroxypyridine. MS: C ₁₉ H ₁₈ ClN about _{5 O 2 S (M + H} ) + as the measured value: 416.1,418.1.

標題化合物を、実施例290に記載のものと同じ方法により、3-フルオロ-2-ヒドロキシピリジンの代わりに3-モルホリノンを用いて調製した。MS：C₁₈H₁₆ClN₅O₃Sについて(M+H)+としての実測値：418.1、420.1。 Example 301
5-Chloro-N-((1- (4- (3-oxomorpholino) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by the same method as described in Example 290 using 3-morpholinone instead of 3-fluoro-2-hydroxypyridine. _{MS: C 18 H 16 ClN 5} O 3 for S (M + H) + as the measured value: 418.1,420.1.

標題化合物を、実施例290に記載のものと同じ方法により、3-フルオロ-2-ヒドロキシピリジンの代わりに3-チオモルホリノンを用いて調製した。MS：C₁₈H₁₆ClN₅O₂S₂について(M+H)+としての実測値：434.0、436.0。 Example 302
5-Chloro-N-((1- (4- (3-oxothiomorpholino) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by the same method as described in Example 290 using 3-thiomorpholinone instead of 3-fluoro-2-hydroxypyridine. _{MS: C 18 H 16 ClN 5} O 2 for S ₂ (M + H) + as the measured value: 434.0,436.0.

標題化合物を、実施例290に記載のものと同じ方法により、3-フルオロ-2-ヒドロキシピリジンの代わりに1,4-オキサゼパン-5-オンを用いて調製した。MS：C₁₉H₁₈ClN₅O₃Sについて(M+H)+としての実測値：432.1、434.1。 Example 303
5-Chloro-N-((1- (4- (5-oxo-1,4-oxazepan-4-yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2 -Carboxamide

The title compound was prepared by the same method as described in Example 290 using 1,4-oxazepan-5-one instead of 3-fluoro-2-hydroxypyridine. _{MS: C 19 H 18 ClN 5} O 3 for S (M + H) + as the measured value: 432.1,434.1.

標題化合物を、スキーム5の実施例290に記載の化合物35と同じ方法により、4-ヨードアニリンの代わりに4-ヨード-2-フルオロアニリンを用いて調製した。MS：C₁₄H₉ClFIN₄OSについて(M+H)+としての実測値：462.0、464.0。 Example 304
5-Chloro-N-((1- (2-fluoro-4-iodophenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by the same method as Compound 35 described in Example 290 of Scheme 5, substituting 4-iodo-2-fluoroaniline for 4-iodoaniline. MS: C ₁₄ H ₉ ClFIN about ₄ OS (M + H) + as the measured value: 462.0,464.0.

実施例304(50mg、0.11mmol)および2-ヒドロキシピリジン(42mg、0.44mmol)を1.2mLの無水ジオキサンおよび0.5mLの無水DMSOに密封試験管中で溶解した。これにN,N'-ジメチルエチレンジアミン(12μL、0.11mmol)、CuI(11mg、0.055mmol)およびK₃PO₄(47mg、0.22mmol)を加えた。混合物を120℃の浴中で2.5時間撹拌した。混合物をろ過し、ろ液を調製用逆相HPLCに直接かけ、標題化合物を収率50〜65％で単離した。MS：C₁₉H₁₃ClFN₅O₂Sについて(M+H)+としての実測値：430.0、432.0。 Example 305
5-Chloro-N-((1- (2-fluoro-4- (2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide

Example 304 (50 mg, 0.11 mmol) and 2-hydroxypyridine (42 mg, 0.44 mmol) were dissolved in 1.2 mL anhydrous dioxane and 0.5 mL anhydrous DMSO in a sealed tube. To this was added N, N′-dimethylethylenediamine (12 μL, 0.11 mmol), CuI (11 mg, 0.055 mmol) and K ₃ PO ₄ (47 mg, 0.22 mmol). The mixture was stirred in a 120 ° C. bath for 2.5 hours. The mixture was filtered and the filtrate was directly subjected to preparative reverse phase HPLC to isolate the title compound in 50-65% yield. MS: C ₁₉ H ₁₃ ClFN for _{5 O 2 S (M + H} ) + as the measured value: 430.0,432.0.

標題化合物を、実施例305に記載のものと同じ方法により、2-ヒドロキシピリジンの代わりに3-モルホリノンを用いて調製した。MS：C₁₈H₁₅ClFN₅O₃Sについて(M+H)+としての実測値：436.1、438.1。 Example 306
5-chloro-N-((1- (2-fluoro-4- (3-oxomorpholino) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by the same method as described in Example 305 using 3-morpholinone instead of 2-hydroxypyridine. _{MS: C 18 H 15 ClFN 5} O 3 for S (M + H) + as the measured value: 436.1,438.1.

実施例305(58mg、0.13mmol)を2mLのDMSOおよび1mLの水に密封試験管中で溶解した。これにCs₂CO₃(88mg、0.26mmol)を加えた。混合物を120℃の浴中で終夜撹拌した。これを室温まで冷却し、逆相HPLCに直接かけ、凍結乾燥後に標題化合物を白色粉末で単離した。MS：C₁₉H₁₄ClN₅O₃Sについて(M+H)+としての実測値：428.1.0、430.1。 Example 307
5-Chloro-N-((1- (2-hydroxy-4- (2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide

Example 305 (58 mg, 0.13 mmol) was dissolved in 2 mL DMSO and 1 mL water in a sealed tube. To this was added Cs ₂ CO ₃ (88 mg, 0.26 mmol). The mixture was stirred in a 120 ° C. bath overnight. This was cooled to room temperature, directly subjected to reverse phase HPLC, and the title compound was isolated as a white powder after lyophilization. _{MS: C 19 H 14 ClN 5} O 3 for S (M + H) + as the measured value: 428.1.0,430.1.

実施例305(58mg、0.13mmol)を2mLの無水DMSO水に密封試験管中で溶解した。これにN-メチルピペラジン(44μL、0.40mmol)およびCs₂CO₃(88mg、0.26mmol)を加えた。混合物を120℃の浴中で終夜撹拌した。これを室温まで冷却し、逆相HPLCに直接かけ、凍結乾燥後に標題化合物を白色粉末で単離した。MS：C₂₄H₂₄ClN₇O₂Sについて(M+H)+としての実測値：510.1、512.1。 Example 308
5-Chloro-N-((1- (2- (4-methylpiperazin-1-yl) -4- (2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3- Triazol-4-yl) methyl) thiophene-2-carboxamide

Example 305 (58 mg, 0.13 mmol) was dissolved in 2 mL anhydrous DMSO water in a sealed tube. To this was added N-methylpiperazine (44 μL, 0.40 mmol) and Cs ₂ CO ₃ (88 mg, 0.26 mmol). The mixture was stirred in a 120 ° C. bath overnight. This was cooled to room temperature, directly subjected to reverse phase HPLC, and the title compound was isolated as a white powder after lyophilization. _{MS: C 24 H 24 ClN 7} O 2 for S (M + H) + as the measured value: 510.1,512.1.

Example 309
5-Chloro-N-((1- (5- (2-oxopyridin-1 (2H) -yl) pyridin-2-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-Carboxamide (40)
Scheme 6

Stage 1:
2-Fluoro-5-bromopyridine (2.18 g, 12.3 mmol) was dissolved in 25 mL anhydrous DMSO. To this was added NaN ₃ (1.61 g, 24.6 mmol) and the mixture was stirred in a 120 ° C. bath overnight. This was diluted with 300 mL of ETOAc and washed 3 times with brine. The organic phase was dried and concentrated in vacuo to give compound 38 (1.00 g, 41%) in high purity. MS: for _{C 5 H 3 BrN 4 (M} + H) + as the measured value: 199.0,201.0.

Stage 2:
Azidopyridine 38 (65 mg, 0.33 mmol) and alkyne 34 (see Example 290 and Scheme 5; 66 mg, 0.33 mmol) were dissolved in 4 mL anhydrous MeOH in a sealed tube. To this was added DIPEA (0.29 L, 1.64 mmol) and CuI (312 mg, 1.64 mmol). The mixture was stirred in a 100 ° C. bath for 3 hours and cooled to room temperature. This was diluted with 200 mL of acetone, stirred well and filtered to remove insoluble copper salts. The filtrate was concentrated under reduced pressure and purified by flash column to give 1,4-disubstituted triazole 39 (52 mg, 40%). MS: C ₁₃ H ₉ BrClN about ₅ OS (M + H) + as the measured value: 398.0,400.0.

Stage 3:
Aryl bromide 39 (52 mg, 0.13 mmol) and 2-hydroxypyridine (37 mg, 0.39 mmol) were dissolved in 2 mL anhydrous dioxane and 2 mL anhydrous DMSO in a sealed tube. To this was added N, N′-dimethylethylenediamine (14 μL, 0.13 mmol), CuI (13 mg, 0.07 mmol) and K ₃ PO ₄ (55 mg, 0.26 mmol). The mixture was stirred in a 120 ° C. bath overnight. This was then filtered and the filtrate was directly subjected to preparative reverse phase HPLC, and the title compound 40 was isolated as a white powder after lyophilization (yield 50%). MS: C ₁₈ H ₁₃ ClN about _{6 O 2 S (M + H} ) + as the measured value: 413.1,415.1.

Example 310
5-Chloro-N-((3- (6- (2-oxopyridin-1 (2H) -yl) pyridin-3-yl) isoxazol-5-yl) methyl) thiophene-2-carboxamide (44)
Scheme 7

Stage 1:
2-Chloropyridine-5-carbaldehyde (3.00 g, 21.2 mmol) was dissolved in 20 mL pyridine and 20 mL ethanol. To this was added hydroxylamine hydrochloride (1.48 g, 21.1 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The dry residue was dissolved in 50 mL anhydrous DMF and stirred in an ice bath. To this was added NCS (3.25 g, 24.4 mmol). The mixture was stirred overnight and diluted with 600 mL of EtOAc. This was washed 4 times with brine, dried and concentrated in vacuo to give compound 42 as a high purity white solid (quantitative yield). _{MS: C 6 H 4 Cl 2} N For ₂ O (M + H) + as the measured value: 191.0,193.0.

Stage 2:
Compound 42 (3.80 g, 20 mmol) and alkyne 34 (see Example 290 and Scheme 5; 3.98 g, 20 mmol) were dissolved in 200 mL of anhydrous toluene. To this was added triethylamine (3.4 mL, 24 mmol). The mixture was refluxed for 3 hours and cooled to room temperature. A white solid (compound 43) precipitated and was collected by filtration. This was washed with cold toluene and dried under reduced pressure. _{MS: C 14 H 9 Cl 2} N 3 O 2 S for (M + H) + as the measured value: 354.0,356.0.

Stage 3:
Compound 43 (53 mg, 0.15 mmol) and 2-hydroxypyridine (43 mg, 0.45 mmol) were dissolved in 2 mL anhydrous DMSO in a sealed tube. To this was added Cs ₂ CO ₃ (73 mg, 0.22 mmol). The mixture was stirred in a 100 ° C. bath overnight. This was then filtered and the filtrate was subjected directly to preparative reverse phase HPLC, and the title compound 44 was isolated as a white powder after lyophilization (yield 40%). _{MS: C 19 H 13 ClN 4} O 3 for S (M + H) + as the measured value: 413.0,415.0.

Example 311
5-chloro-N-((3- (4- (2-oxopyridin-1 (2H) -yl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) thiophene-2-carboxamide (51 )
Scheme 8

Stage 1:
4-Iodobenzonitrile (3.00 g, 13 mmol) and 2-hydroxypyridine (2.47 g, 26 mmol) were dissolved in 30 mL anhydrous DMSO in a sealed tube. To this was added 8-hydroxyquinoline (0.57 g, 4 mmol), CuI (0.74 g, 4 mmol) and Cs ₂ CO ₃ (8.5 g, 26 mmol). The mixture was stirred in a 120 ° C. bath overnight. The mixture was partitioned between 500 mL EtOAc and 250 mL water. The organic phase was separated and the aqueous phase was extracted 3 times with EtOAc. All organic phases were combined, dried, concentrated and purified using a flash column to give compound 46 (1.67 g, 66%). MS: for _{C 12 H 8 N 2 O (} M + H) + as the measured value: 197.1.

Stage 2:
Compound 46 (1.67 g, 8.5 mmol) was dissolved in 40 mL DMSO. To this was added DIPEA (7.5 mL, 42.6 mmol) and hydroxylamine hydrochloride (3.0 g, 42.6 mmol). The mixture was stirred for 3 hours, to which 250 mL of brine was added. A white solid (compound 47) was broken up and collected. This was washed with brine and cold water and dried in vacuo overnight. MS: C ₁₂ H ₁₁ For _{N 3 O 2 (M + H} ) + as the measured value: 230.1.

Stage 3:
Glycine methyl ester hydrochloride (48, 2.00 g, 16 mmol) and 5-chlorothiophene-2-carboxylic acid (2.60 g, 16 mmol) were dissolved in 50 mL of pyridine and stirred in an ice bath. To this was added POCl ₃ (4.5 mL, 48 mmol) dropwise. After 5 minutes, ice pieces were added to the mixture followed by 500 mL of water. The mixture was stirred well and filtered. The aqueous filtrate was extracted 4 times with EtOAc. All organic phases were combined, dried and concentrated in vacuo to give compound 49 as a pale yellow solid (2.27 g, 61%). MS: C ₈ H ₈ ClNO ₃ for S (M + H) + as the measured value: 234.0,236.0.

Stage 4:
Methyl ester 49 (2.27 g, 9.7 mmol) was dissolved in 20 mL MeOH, 20 mL dioxane and 20 mL water. To this was added lithium hydroxide monohydrate (1.22 g, 29 mmol). The mixture was stirred at room temperature for 2 hours and acidified with 2M HCl to pH = 7. The neutral mixture was concentrated under reduced pressure to remove the organic solvent. The aqueous residue was extracted 4 times with EtOAc. The organic phases were combined, dried and concentrated in vacuo to give acid 50 in quantitative yield. MS: C ₇ H ₆ ClNO ₃ for S (M + H) + as the measured value: 220.0,222.0.

Stage 5:
Acid 50 (219 mg, 1.0 mmol) was dissolved in 10 mL anhydrous DMF. To this was added carbonyldiimidazole (180 mg, 1.1 mmol). The mixture was stirred at room temperature for 1 hour. To this was then added compound 47 (229 mg, 1.0 mmol). The mixture was stirred at room temperature for 30 minutes and slowly heated to 120 ° C. in an oil bath. This was then stirred for 2 hours. After cooling to room temperature, 50 mL of brine was added to the mixture. The mixture was extracted 4 times with EtOAc. All organic phases were combined, dried and concentrated in vacuo. The resulting mixture was purified by preparative reverse phase HPLC to give the title compound 51. _{MS: C 19 H 13 ClN 4} O 3 for S (M + H) + as the measured value: 413.0,415.0.

Example 312
5-Chloro-N-((1- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl Thiophene-2-carboxamide (55)
Scheme 9

Stage 1:
4-Aminobenzonitrile (52, 2.0 g, 17 mmol) was dissolved in 8 mL of TFA and stirred in an ice bath. To this was added NaNO ₂ (1.3 g, 18.7 mmol) in small portions. The mixture was stirred in an ice bath for 30 minutes. NaN ₃ (1.1 g, 17 mmol) was then dissolved in 6 mL water and cooled in ice. This solution was added into the reaction mixture. After stirring in an ice bath for 1 hour, the mixture was concentrated under reduced pressure to remove TFA and diluted with water. The aqueous mixture was extracted 3 times with DCM. The organic phases were combined, dried and concentrated in vacuo to give compound 53 (2.35 g, 96%). MS: for _{C 7 H 4 N 4 (M} + H) + as the measured value: 145.0.

Stage 2:
Azidobenzene 53 (1.77 g, 12.3 mmol) and alkyne 34 (see Scheme 5 in Example 290; 2.45 g, 12.3 mmol) were refluxed in 200 mL of toluene overnight. The mixture was then concentrated in vacuo to half volume and cooled in an ice bath. The precipitated solid was the pure main product 1,4-disubstituted triazole 54, which was filtered and washed with cold toluene. The by-product (corresponding 1,5-triazole isomer) remains completely in the filtrate with some 1,4-disubstituted triazole 54, which is a result of multiple recrystallization steps using DCM or EtOAc as the solvent. Further recovery was possible. The 1,4-disubstituted triazole 54 was dried under reduced pressure. MS: C ₁₅ H ₁₀ ClN about ₅ OS (M + H) + as the measured value: 344.0,346.0.

Stage 3:
1,4-disubstituted triazole 54 (100 mg, 0.29 mmol) was dissolved in 50 mL anhydrous dioxane and 20 mL triethylamine. The solution was aerated with dry H ₂ S gas until saturated. The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was added to 50 mL anhydrous acetone. To this was added 1.0 mL of iodomathane. The mixture was refluxed for 1.5 hours and concentrated in vacuo. The residue was then dissolved in 20 mL anhydrous methanol. To this was added 0.5 mL acetic acid and 0.2 mL N-methylethylenediamine. The mixture was refluxed for 1 hour, concentrated in vacuo, subjected to preparative reverse phase HPLC, and the title compound 55 was isolated as a white powder after lyophilization. MS: C ₁₈ H ₁₇ ClN about ₆ OS (M + H) + as the measured value: 401.1,403.1.

標題化合物を、実施例312のスキーム9に記載のものと同じ方法により、N-メチルエチレンジアミンの代わりにジメチルアミンを用いて調製した。MS：C₁₇H₁₇ClN₆OSについて(M+H)+としての実測値：389.1、391.1。 Example 313
N-((1- (4- (N, N-dimethylcarbamimidoyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by the same method described in Scheme 9 of Example 312 using dimethylamine instead of N-methylethylenediamine. MS: C ₁₇ H ₁₇ ClN about ₆ OS (M + H) + as the measured value: 389.1,391.1.

標題化合物を、実施例312のスキーム9に記載のものと同じ方法により、N-メチルエチレンジアミンの代わりにN-エチル-N-メチルアミンを用いて調製した。MS：C₁₈H₁₉ClN₆OSについて(M+H)+としての実測値：403.1、405.1。 Example 314
N-((1- (4- (N-ethyl-N-methylcarbamimidoyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by the same method described in Scheme 9 of Example 312 using N-ethyl-N-methylamine instead of N-methylethylenediamine. MS: C ₁₈ H ₁₉ ClN about ₆ OS (M + H) + as the measured value: 403.1,405.1.

標題化合物を、実施例312のスキーム9に記載のものと同じ方法により、N-メチルエチレンジアミンの代わりにN-メチル-N-プロピルアミンを用いて調製した。MS：C₁₉H₂₁ClN₆OSについて(M+H)+としての実測値：417.1、419.1。 Example 315
N-((1- (4- (N-methyl-N-propylcarbamimidoyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by the same method described in Scheme 9 of Example 312 using N-methyl-N-propylamine instead of N-methylethylenediamine. MS: C ₁₉ H ₂₁ ClN about ₆ OS (M + H) + as the measured value: 417.1,419.1.

標題化合物を、実施例312のスキーム9に記載のものと同じ方法により、N-メチルエチレンジアミンの代わりにN-(2-メトキシエチル)-N-メチルアミンを用いて調製した。MS：C₁₉H₂₁ClN₆O₂Sについて(M+H)+としての実測値：433.1、435.1。 Example 316
N-((1- (4- (N- (2-methoxyethyl) -N-methylcarbamimidoyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chloro Thiophene-2-carboxamide

The title compound was prepared by the same method described in Scheme 9 of Example 312 using N- (2-methoxyethyl) -N-methylamine instead of N-methylethylenediamine. MS: C ₁₉ H ₂₁ ClN about _{6 O 2 S (M + H} ) + as the measured value: 433.1,435.1.

標題化合物を、実施例312のスキーム9に記載のものと同じ方法により、N-メチルエチレンジアミンの代わりにアゼチジンを用いて調製した。MS：C₁₈H₁₇ClN₆OSについて(M+H)+としての実測値：401.1、403.1。 Example 317
N-((1- (4- (azetidin-1-yl (imino) methyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by the same method as described in Scheme 3 of Example 312 using azetidine instead of N-methylethylenediamine. MS: C ₁₈ H ₁₇ ClN about ₆ OS (M + H) + as the measured value: 401.1,403.1.

標題化合物を、実施例312のスキーム9に記載のものと同じ方法により、N-メチルエチレンジアミンの代わりにピロリジンを用いて調製した。MS：C₁₉H₁₉ClN₆OSについて(M+H)+としての実測値：415.1、417.1。 Example 318
5-Chloro-N-((1- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by the same method described in Scheme 9 of Example 312 using pyrrolidine instead of N-methylethylenediamine. MS: C ₁₉ H ₁₉ ClN about ₆ OS (M + H) + as the measured value: 415.1,417.1.

標題化合物を、実施例312のスキーム9に記載のものと同じ方法により、N-メチルエチレンジアミンの代わりにピペリジンを用いて調製した。MS：C₂₀H₂₁ClN₆OSについて(M+H)+としての実測値：429.1、431.1。 Example 319
5-Chloro-N-((1- (4- (imino (piperidin-1-yl) methyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by the same method described in Scheme 9 of Example 312 using piperidine instead of N-methylethylenediamine. MS: C ₂₀ H ₂₁ ClN about ₆ OS (M + H) + as the measured value: 429.1,431.1.

Example 320
N-((1- (4- (N, N-dimethylcarbamimidoyl) -2-fluorophenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2 -Carboxamide (59)
Scheme 10

Stage 1:
To a solution of 4-amino-3-fluorobenzonitrile (56, 1.0 g, 7.35 mmol) in TFA (5 mL) at 0 ° C. was added NaNO ₂ (558 mg, 8.09 mmol) in small portions. The reaction mixture was stirred at 0 ° C. for 0.5 h. A solution of NaN ₃ (478 mg, 7.35 mmol) in water (4 mL) was then added. The resulting mixture was stirred at 0 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, then neutralized with saturated aqueous NaHCO ₃ solution to pH = 7, and extracted three times with DCM. The combined organic phases were washed with water and brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure to give compound 57 (0.94 g, 79%).

Stage 2:
A solution of azidobenzene 57 (0.94 g, 5.80 mmol) and alkyne 34 (see Scheme 5 in Example 290; 1.3 g, 6.53 mmol) in toluene (30 mL) was refluxed for 3 hours and concentrated in vacuo. The residue was dissolved in chloroform, washed with water and brine, dried, evaporated and subjected to flash column chromatography to give compound 58. MS: C ₁₅ H ₉ ClFN about ₅ OS (M ⁺ Na) + as the measured value: 384.0,386.0.

Stage 3:
A solution of compound 58 (111 mg, 0.31 mmol) in triethylamine (1.2 mL) and dioxane (12 mL) was bubbled with dry H ₂ S gas to saturation. The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was added to 10 mL anhydrous acetone followed by 0.4 mL iodomethane. The reaction mixture was refluxed for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 9 mL anhydrous methanol. To this was added 0.2 mL acetic acid and dimethylamine (0.8 mL, 2.0 M in THF). The resulting mixture was refluxed for 1 hour, concentrated in vacuo and subjected to preparative reverse phase HPLC to give the title compound 59 as a white powder after lyophilization. MS: C ₁₇ H ₁₆ ClFN about ₆ OS (M + H) + as the measured value: 407.1,409.1.

標題化合物を、実施例320のスキーム10に記載のものと同じ方法により、ジメチルアミンの代わりにアゼチジンを用いて調製した。MS：C₁₈H₁₆ClFN₆OSについて(M+H)+としての実測値：419.1、421.1。 Example 321
N-((1- (4- (azetidin-1-yl (imino) methyl) -2-fluorophenyl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2 -Carboxamide

The title compound was prepared by the same method described in Scheme 10 of Example 320 using azetidine instead of dimethylamine. MS: C ₁₈ H ₁₆ ClFN about ₆ OS (M + H) + as the measured value: 419.1,421.1.

標題化合物を、実施例320のスキーム10に記載のものと同じ方法により、ジメチルアミンの代わりにピロリジンを用いて調製した。MS：C₁₉H₁₈ClFN₆OSについて(M+H)+としての実測値：433.1、435.1。 Example 322
5-Chloro-N-((1- (2-fluoro-4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2 -Carboxamide

The title compound was prepared by the same method described in Example 320, Scheme 10, using pyrrolidine instead of dimethylamine. MS: C ₁₉ H ₁₈ ClFN about ₆ OS (M + H) + as the measured value: 433.1,435.1.

標題化合物を、実施例320のスキーム10に記載のものと同じ方法により、ジメチルアミンの代わりにピペリジンを用いて調製した。MS：C₂₀H₂₀ClFN₆OSについて(M+H)+としての実測値：447.1、449.1。 Example 323
5-Chloro-N-((1- (2-fluoro-4- (imino (piperidin-1-yl) methyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2 -Carboxamide

The title compound was prepared by the same method described in Scheme 10 of Example 320 using piperidine instead of dimethylamine. MS: C ₂₀ H ₂₀ ClFN about ₆ OS (M + H) + as the measured value: 447.1,449.1.

標題化合物を、実施例320のスキーム10に記載のものと同じ方法により、ジメチルアミンの代わりにN-メチルエチレンジアミンを用いて調製した。MS：C₁₈H₁₆ClFN₆OSについて(M+H)+としての実測値：419.1、421.1。 Example 324
5-Chloro-N-((1- (2-fluoro-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1H-1,2,3-triazole-4 -Yl) methyl) thiophene-2-carboxamide

The title compound was prepared by the same method described in Scheme 10 of Example 320 using N-methylethylenediamine instead of dimethylamine. MS: C ₁₈ H ₁₆ ClFN about ₆ OS (M + H) + as the measured value: 419.1,421.1.

Example 325
N-((1- (4- (N, N-dimethylcarbamimidoyl) phenyl) -1H-pyrazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide (66)
Scheme 11

Stage 1:
4-Cyanobenzeneboronic acid (60, 3.6 g, 24 mmol), 4-methylpyrazole (2.0 mL, 24 mmol), pyridine (5.8 mL, 72 mmol), Cu (OAc) ₂ (8.7 g, 48 mmol) in chloroform (100 mL) ) And the activated molecular sieve powder were refluxed for 24 hours. The reaction was not complete. The mixture was filtered and the solid cake was washed with a large amount of methanol. The filtrate was concentrated under reduced pressure and purified by flash column to give compound 61 as a white powder (0.93 g, 21%). MS: for _{C 11 H 9 N 3 (M} + H) + as the measured value: 184.1.

Stage 2:
Compound 61 (0.89 g, 4.8 mmol) was dissolved in 100 mL CCl ₄ . To this was added NBS (1.3 g, 7.3 mmol) and benzoyl peroxide (1.18 g, 4.8 mmol). The mixture was refluxed for 1 hour and concentrated in vacuo. The residue was subjected to flash column chromatography to give compound 62 (0.33 g, 26%). MS: for _{C 11 H 8 BrN 3 (M} + H) + as the measured value: 262.0,264.0.

Stage 3:
Compound 62 (0.33 g, 1.26 mmol) was dissolved in 6 mL anhydrous DMF. To this was added NaN ₃ (164 mg, 2.52 mmol). The mixture was stirred for 2 hours and added to 200 mL EtOAc. This was washed with water and brine, dried, concentrated and purified by flash column to give compound 63 (0.27 g, 96%). MS: for _{C 11 H 8 N 6 (M} + H) + as the measured value: 225.1.

Stage 4:
Compound 63 (0.27 g, 1.2 mmol) was dissolved in 10 mL THF and 20 mL MeOH. To this was added tin (II) chloride dihydrate (0.54 g, 2.4 mmol). The mixture was refluxed for 2 hours and diluted with 500 mL of chloroform. This was washed with 0.1 N NaOH and water, dried, concentrated and purified by reverse phase HPLC to give compound 64 (0.13 g, 55%). MS: for _{C 11 H 10 N 4 (M} + H) + as the measured value: 199.1.

Stage 5:
Compound 64 (0.13 g, 0.66 mmol) was dissolved in 12 mL anhydrous pyridine. To this was added 5-chlorothiophene-2-carbonyl chloride (0.24 g, 1.32 mmol). The mixture was stirred at room temperature for 2 hours, concentrated in vacuo and purified using a flash column to give compound 65 (0.22 g, 99%). _{MS: C 16 H 11 ClN 4} OS for (M + H) + as the measured value: 343.0,345.0.

Stage 6:
Compound 65 (100 mg, 0.30 mmol) was added to 50 mL anhydrous methanol in an ice bath. This was aerated with dry HCl gas until saturated. The mixture was stirred at room temperature overnight and concentrated in vacuo. The dry residue was then dissolved in 50 mL anhydrous methanol. To this was added dimethylamine (1.2 mmol, 2.0 mL dimethylamine / THF solution 0.6 mL). The mixture was refluxed for 1 hour, concentrated in vacuo, purified by reverse phase HPLC to give the title compound 66 as a white powder after lyophilization. MS: C ₁₈ H ₁₈ ClN about ₅ OS (M + H) + as the measured value: 388.1,390.1.

標題化合物を、実施例325のスキーム11に記載のものと同じ方法により、ジメチルアミンの代わりにN-メチルエチレンジアミンを用いて調製した。MS：C₁₉H₁₈ClN₅OSについて(M+H)+としての実測値：400.1、402.1。 Example 326
5-Chloro-N-((1- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1H-pyrazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by the same method described in Scheme 11 Example 325 using N-methylethylenediamine instead of dimethylamine. MS: C ₁₉ H ₁₈ ClN about ₅ OS (M + H) + as the measured value: 400.1,402.1.

標題化合物を、実施例325のスキーム11に記載のものと同じ方法により、ジメチルアミンの代わりにアゼチジンを用いて調製した。MS：C₁₉H₁₈ClN₅OSについて(M+H)+としての実測値：400.1、402.1。 Example 327
N-((1- (4- (azetidin-1-yl (imino) methyl) phenyl) -1H-pyrazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by the same method described in Scheme 11 Example 325 using azetidine instead of dimethylamine. MS: C ₁₉ H ₁₈ ClN about ₅ OS (M + H) + as the measured value: 400.1,402.1.

標題化合物を、実施例325のスキーム11に記載のものと同じ方法により、ジメチルアミンの代わりにピロリジンを用いて調製した。MS：C₂₀H₂₀ClN₅OSについて(M+H)+としての実測値：414.1、416.1。 Example 328
5-Chloro-N-((1- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1H-pyrazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by the same method described in Scheme 11 Example 325 using pyrrolidine instead of dimethylamine. MS: C ₂₀ H ₂₀ ClN about ₅ OS (M + H) + as the measured value: 414.1,416.1.

標題化合物を、実施例325のスキーム11に記載のものと同じ方法により、ジメチルアミンの代わりにピペリジンを用いて調製した。MS：C₂₁H₂₂ClN₅OSについて(M+H)+としての実測値：428.1、430.1。 Example 329
5-Chloro-N-((1- (4- (imino (piperidin-1-yl) methyl) phenyl) -1H-pyrazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by the same method described in Scheme 11 Example 325 using piperidine instead of dimethylamine. MS: C ₂₁ H ₂₂ ClN about ₅ OS (M + H) + as the measured value: 428.1,430.1.

Example 330
N-((5- (4- (N, N-dimethylcarbamimidoyl) phenyl) isoxazol-3-yl) methyl) -5-chlorothiophene-2-carboxamide (74).
Scheme 12

Stage 1:
Performed in the same manner as Example 1, Step 1. Compound 68 was used immediately without purification.

Stage 2:
Performed in the same manner as Example 1, Step 2. Crude compound 69 was used for step 5.

Stage 3:
Aryl bromide 70 (5.00 g, 27 mmol) was mixed with CuI (0.10 g, 0.55 mmol), tri-t-butylphosphine (0.41 mL, 1.6 mmol) and Pd (PhCN) ₂ Cl ₂ (0.32 g, 0.82 mmol). . Degassed for 3 minutes, then TMS acetylene (4.6 mL, 33 mmol) and diisopropylamine (9.5 mL, 68 mmol) were added and the reaction mixture turned from light beige to black with the addition of amine. After stirring for 3 hours, all starting bromide was consumed as confirmed by HPLC. The reaction mixture was filtered through a short silica gel pad (eluting with dichloromethane) and concentrated. The resulting semi-solid was triturated with 20 mL hexanes to give the desired product (71) as a brown solid (2.51 g, 47%).

Stage 4:
TMS protected alkyne 71 (1.35 g, 1.01 mmol) was diluted with 10 mL THF and treated with 1M tetrabutylammonium fluoride in THF (1.1 mL, 1.1 mmol). After 30 minutes, HPLC confirmed complete consumption of starting material and a highly polar spot. The reaction mixture was diluted with 90 mL water and 10 mL 1M aqueous HCl. The resulting solid was filtered and washed with water to give 72 as a brown solid (0.6237 g, 49%).

Stage 5:
Alkyne 72 (0.36 g, 2.87 mmol) and triethylamine (0.60 mL, 4.31 mmol) were diluted with 10 mL toluene and heated to 100 ° C. To this solution 69 was slowly added as a crude reaction mixture from Step 3. After the addition was complete, the reaction was checked by TLC and about 50% reaction was confirmed. The reaction mixture was cooled and partitioned with 1M HCl and ethyl acetate and separated. The aqueous phase was extracted again with ethyl acetate and the combined organic layers were filtered through a short silica gel pad and concentrated. The resulting brown oil was then purified by silica gel chromatography (10% ethyl acetate / dichloromethane) to give isoxazole 73 as an off-white solid (0.37 g, 41%).

Stage 6:
Performed in the same manner as Example 8. _{MS: C 18 H 17 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 389.1,391.1.

標題化合物を、実施例330のスキーム12に記載のものと同様の方法により調製した。MS：C₁₉H₁₇ClN₄O₂Sについて(M+H)+としての実測値：401.0、403.0。 Example 331
5-chloro-N-((5- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) isoxazol-3-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Scheme 12 of Example 330. _{MS: C 19 H 17 ClN 4} O 2 for S (M + H) + as the measured value: 401.0,403.0.

標題化合物を、実施例330のスキーム12に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：415.0、417.0。 Example 332
5-chloro-N-((5- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) isoxazol-3-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Scheme 12 of Example 330. _{MS: C 20 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 415.0,417.0.

標題化合物を、実施例330のスキーム12に記載のものと同様の方法により調製した。MS：C₂₁H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：429.0、431.1。 Example 333
5-chloro-N-((5- (4- (imino (piperidin-1-yl) methyl) phenyl) isoxazol-3-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Scheme 12 of Example 330. _{MS: C 21 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 429.0,431.1.

Example 334
N-((3- (4- (N, N-dimethylcarbamimidoyl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) -5-chlorothiophene-2-carboxamide (80)
Scheme 13

Stage 1:
3 (4.13 g, 23 mmol) and dioxane (40 mL) were mixed. To this was added gaseous NH ₃ in constant flow for 2 minutes, during which time a white precipitate formed. After 5 minutes, the reaction was checked by HPLC to confirm complete consumption of starting chloride. The reaction mixture was diluted with a small amount of ether and filtered, then the filtrate was concentrated to give the desired product 75 as a pale yellow powder (3.27 g, 89%).

Stage 2:
Boc protected glycine (76) (0.54 g, 3.11 mmol) was mixed with 75 (0.50 g, 3.11 mmol) and 5 mL of DMF followed by carbonyldiimidazole (0.604 g, 3.73 mmol) and gas evolved. The mixture was stirred at room temperature for 1 hour and then heated to 110 ° C. After 30 minutes, CDI was added to the heated mixture (0.600 g, 3.73 mmol) and gas evolved again. The reaction was checked by HPLC and a complete consumption of 75 and a new peak was confirmed. The reaction mixture was diluted with water and filtered, and the solid was washed with water and a small amount of methanol (it appeared to dissolve the product) to give the desired product (77) as a white solid (0.335 g 36%).

Stage 3:
Performed in the same manner as Example 49, Step 5.

Stage 4:
Performed in the same manner as Example 325, Step 5.

Stage 5:
Performed in the same manner as Example 325, Step 6. MS: C ₁₇ H ₁₆ ClN about _{5 O 2 S (M + H} ) + as the measured value: 390.8,392.5.

標題化合物を、実施例334に記載のものと同様の方法により調製した。MS：C₁₈H₁₆ClN₅O₂Sについて(M+H)+としての実測値：402.1、404.1。 Example 335
5-Chloro-N-((3- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) thiophene -2-carboxamide

The title compound was prepared by a method similar to that described in Example 334. MS: C ₁₈ H ₁₆ ClN about _{5 O 2 S (M + H} ) + as the measured value: 402.1,404.1.

標題化合物を、実施例334に記載のものと同様の方法により調製した。MS：C₁₉H₁₈ClN₅O₂Sについて(M+H)+としての実測値：416.1、418.1。 Example 336
5-Chloro-N-((3- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 334. MS: C ₁₉ H ₁₈ ClN about _{5 O 2 S (M + H} ) + as the measured value: 416.1,418.1.

標題化合物を、実施例334に記載のものと同様の方法により調製した。MS：C₂₀H₂₀ClN₅O₂Sについて(M+H)⁺としての実測値：430.1、432.1。 Example 337
5-Chloro-N-((3- (4- (imino (piperidin-1-yl) methyl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 334. MS: C ₂₀ H ₂₀ ClN about _{5 O 2 S (M + H} ) + as the measured value: 430.1,432.1.

Example 338
N-((2- (4- (N, N-dimethylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide (87).
Scheme 14

Stage 1:
Amide 81 (5.00 g, 31 mmol), dibromoacetone 82 (13 g, 62 mmol) and 60 mL toluene were mixed in a flask equipped with a condenser. The mixture was refluxed overnight and checked the next day by HPLC to confirm complete consumption of starting material. The reaction mixture was concentrated and purified by silica gel chromatography (dichloromethane as eluent) to give the desired product 83 as a beige solid (5.21 g, 60%).

Stage 2:
Bromide 83 (3.94 g, 15 mmol) and 30 mL DMF were mixed. To this was added sodium azide (1.46 g, 23 mmol) and about 10 mg of tetrabutylammonium iodide. The reaction mixture was stirred for 1 hour and then checked by mass spectrometry and only the desired azide was observed. The reaction mixture was diluted with 100 mL water and filtered to give the desired product as a beige solid.

Stage 3:
Azide 84 (1.19 g, 5.3 mmol) was diluted with 20 mL of ethyl acetate. The solution was degassed with argon, treated with about 100 mg of 10% Pd / C and then purged with hydrogen gas (balloon). After 2 hours, all starting materials were consumed as determined by TLC. The mixture was filtered through a short celite pad, concentrated to a beige semi-solid and used immediately in the next step.

Stage 4:
The title compound was prepared by a method similar to that described in Example 325, Step 5.

Stage 5:
The title compound was prepared by a method similar to that described in Example 325, Step 6. _{MS: C 18 H 17 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 389.1,391.1.

標題化合物を、実施例338に記載のものと同様の方法により調製した。MS：C₁₉H₁₇ClN₄O₂Sについて(M+H)⁺としての実測値：401.1、403.1。 Example 339
5-Chloro-N-((2- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) oxazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 338. _{MS: C 19 H 17 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 401.1,403.1.

標題化合物を、実施例338に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：415.1、417.1。 Example 340
5-Chloro-N-((2- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) oxazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 338. _{MS: C 20 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 415.1,417.1.

標題化合物を、実施例338に記載のものと同様の方法により調製した。MS：C₂₁H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：429.1、431.1。 Example 341
5-Chloro-N-((2- (4- (imino (piperidin-1-yl) methyl) phenyl) oxazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 338. _{MS: C 21 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 429.1,431.1.

標題化合物を、実施例338に記載のものと同様の方法により調製した。MS：C₂₄H₂₅ClN₄O₄Sについて(M+H)⁺としての実測値：501.1、503.1。 Example 342
1-((4- (4-((2-Chlorothiophene-5-carboxamido) methyl) oxazol-2-yl) phenyl) (imino) methyl) piperidine-4-carboxylate

The title compound was prepared by a method similar to that described in Example 338. _{MS: C 24 H 25 ClN 4} O 4 for S (M ⁺ H) + as the measured value: 501.1,503.1.

標題化合物を、実施例338に記載のものと同様の方法により調製した。MS：C₁₉H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：403.1、405.1。 Example 343
N-((2- (4- (N-ethyl-N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 338. _{MS: C 19 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 403.1,405.1.

標題化合物を、実施例338に記載のものと同様の方法により調製した。MS：C₂₀H₂₁ClN₄O₂Sについて(M+H)⁺としての実測値：417.1、419.1。 Example 344
N-((2- (4- (N-methyl-N-propylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 338. _{MS: C 20 H 21 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 417.1,419.1.

標題化合物を、実施例338に記載のものと同様の方法により調製した。MS：C₂₁H₂₄ClN₅O₂Sについて(M+H)⁺としての実測値：446.1、448.1。 Example 345
N-((2- (4- (N- (2- (dimethylamino) ethyl) -N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 338. MS: C ₂₁ H ₂₄ ClN about _{5 O 2 S (M + H} ) + as the measured value: 446.1,448.1.

標題化合物を、実施例338に記載のものと同様の方法により調製した。MS：C₂₀H₂₁ClN₄O₃Sについて(M+H)⁺としての実測値：433.1、435.1。 Example 346
N-((2- (4- (N- (2-methoxyethyl) -N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 338. _{MS: C 20 H 21 ClN 4} O 3 for S (M ⁺ H) + as the measured value: 433.1,435.1.

標題化合物を、実施例338に記載のものと同様の方法により調製した。MS：C₂₂H₂₂ClN₅O₃Sについて(M+H)+としての実測値：472.0、474.0。 Example 347
1-((4- (4-((2-chlorothiophene-5-carboxamido) methyl) oxazol-2-yl) phenyl) (imino) methyl) piperidine-4-carboxamide

The title compound was prepared by a method similar to that described in Example 338. _{MS: C 22 H 22 ClN 5} O 3 for S (M + H) + as the measured value: 472.0,474.0.

標題化合物を、実施例338に記載のものと同様の方法により調製した。MS：C₁₇H₁₅ClN₄O₂Sについて(M+H)⁺としての実測値：375.0、377.0。 Example 348
N-((2- (4- (N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 338. _{MS: C 17 H 15 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 375.0,377.0.

標題化合物を、実施例338に記載のものと同様の方法により調製した。MS：C₂₂H₁₉ClN₄O₃Sについて(M+H)⁺としての実測値：455.1、457.1。 Example 349
N-((2- (4- (N- (furan-2-ylmethyl) -N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 338. _{MS: C 22 H 19 ClN 4} O 3 for S (M ⁺ H) + as the measured value: 455.1,457.1.

Example 350
N-((2- (4- (N, N-dimethylcarbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide (94)
Scheme 15

Stage 1:
Amide 81 (0.64 g, 4.1 mmol), Lawson's reagent (1.00 g, 2.4 mmol) and 15 mL of toluene were mixed in a flask equipped with a condenser. The resulting beige suspension was refluxed for 2 hours, at which time all starting amide was consumed as determined by HPLC. The reaction mixture was cooled, filtered through silica gel, concentrated and then purified by eluting through a short silica gel plug (dichloromethane as eluent) to give the desired thioamide (88) as an orange solid (0.260 g, 39 %).

Stage 2:
Thioamide 88 (0.48 g, 30 mmol), dichloroacetone 89 (0.45 g, 36 mmol) and 20 mL ethanol were mixed in a flask equipped with a condenser. The mixture was refluxed for 3 hours, at which time all starting thioamide was consumed as determined by TLC. The mixture was cooled and partitioned with water and ethyl acetate and separated. The aqueous phase was extracted again with ethyl acetate and the combined organic layers were dried over Na ₂ SO ₄ , filtered through a short silica gel pad and concentrated to give a quantitative amount of thiazole 90 as an off-white solid.

Stage 3:
Performed in the same manner as Example 338, Step 2. For _{C 11 H 7 N 5 S (} M + H) + as the measured value: 242.3.

Stage 4:
Performed in the same manner as Example 338, Step 3.

Stage 5:
Performed in the same manner as Example 338, Step 4.

Stage 6:
Performed in the same manner as Example 338, Step 5. MS: C ₁₈ H ₁₇ For _{ClN 4 OS 2 (M + H} ) + as the measured value: 405.0,407.0.

標題化合物を、実施例350に記載のものと同様の方法により調製した。MS：C₁₉H₁₇ClN₄OS₂について(M+H)⁺としての実測値：417.0、419.0。 Example 351
5-Chloro-N-((2- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) thiazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 350. MS: C ₁₉ H ₁₇ For _{ClN 4 OS 2 (M + H} ) + as the measured value: 417.0,419.0.

標題化合物を、実施例350に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClN₄OS₂について(M+H)⁺としての実測値：431.0、433.0。 Example 352
5-Chloro-N-((2- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) thiazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 350. MS: C ₂₀ H ₁₉ For _{ClN 4 OS 2 (M + H} ) + as the measured value: 431.0,433.0.

標題化合物を、実施例350に記載のものと同様の方法により調製した。MS：C₂₁H₂₁ClN₄OS₂について(M+H)⁺としての実測値：445.1、447.0。 Example 353
5-Chloro-N-((2- (4- (imino (piperidin-1-yl) methyl) phenyl) thiazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 350. MS: C ₂₁ H ₂₁ For _{ClN 4 OS 2 (M + H} ) + as the measured value: 445.1,447.0.

標題化合物を、実施例350に記載のものと同様の方法により調製した。MS：C₂₄H₂₅ClN₄O₃S₂について(M+H)⁺としての実測値：517.1、519.1。 Example 354
1-((4- (4-((2-Chlorothiophene-5-carboxamido) methyl) thiazol-2-yl) phenyl) (imino) methyl) piperidine-4-carboxylate

The title compound was prepared in a similar manner as described in Example 350. MS: C ₂₄ H ₂₅ For _{ClN 4 O 3 S 2 (M} + H) + as the measured value: 517.1,519.1.

標題化合物を、実施例350に記載のものと同様の方法により調製した。MS：C₂₁H₂₄ClN₅OS₂について(M+H)⁺としての実測値：462.1、464.1。 Example 355
N-((2- (4- (N- (2- (dimethylamino) ethyl) -N-methylcarbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 350. MS: C ₂₁ H ₂₄ ClN about _{5 OS 2 (M + H)} + as the measured value: 462.1,464.1.

標題化合物を、実施例350に記載のものと同様の方法により調製した。MS：C₂₂H₁₉ClN₄O₂S₂について(M+H)⁺としての実測値：471.0、473.0。 Example 356
N-((2- (4- (N- (furan-2-ylmethyl) -N-methylcarbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 350. _{MS: C 22 H 19 ClN 4} O 2 for S ₂ (M ⁺ H) + as the measured value: 471.0,473.0.

標題化合物を、実施例350に記載のものと同様の方法により調製した。MS：C₂₀H₁₇ClN₄OS₂について(M+H)⁺としての実測値：429.0、431.0。 Example 357
N-((2- (4- (N-methyl-N- (prop-2-ynyl) carbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 350. MS: C ₂₀ H ₁₇ For _{ClN 4 OS 2 (M + H} ) + as the measured value: 429.0,431.0.

標題化合物を、実施例350に記載のものと同様の方法により調製した。MS：C₁₇H₁₅ClN₄OS₂について(M+H)⁺としての実測値：391.0、393.0。 Example 358
N-((2- (4- (N-methylcarbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 350. MS: C ₁₇ H ₁₅ For _{ClN 4 OS 2 (M + H} ) + as the measured value: 391.0,393.0.

Example 359
5-Chloro-N-((4- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) oxazol-2-yl) methyl) thiophene-2-carboxamide (103)
Scheme 16

Stage 1:
Compound 95 (2.24 g, 10 mmol) and compound 96 (0.59 g, 10 mmol) were refluxed in ethanol overnight. The mixture was concentrated under reduced pressure and subjected to flash column chromatography to give compound 97.

Stage 2:
97 (0.115 g, 0.62 mmol), N-bromosuccinimide (0.11 g, 0.62 mmol) and carbon tetrachloride were mixed in a flask equipped with a condenser. To this was added a small amount (about 10 mg) of benzoyl peroxide and the mixture was heated to reflux overnight. The next day, the reaction was checked by TLC to confirm complete consumption of starting material and a new, less polar spot. The crude reaction mixture was adsorbed onto a silica gel plug, eluted with dichloromethane and examined by NMR to give 5-substituted bromide 98 as the main product.

Stage 3:
Performed in the same manner as step 2 to give compound 99.

Stage 4:
Performed in the same manner as Example 338, Step 2.

Stage 5:
Performed in the same manner as Example 338, Step 3.

Stage 6:
Performed in the same manner as Example 338, Step 4.

Stage 7:
Performed in the same manner as Example 338, Step 5. _{MS: C 20 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 415.0,417.0.

標題化合物を、実施例359に記載のものと同様の方法により調製した。MS：C₁₈H₁₇ClN₄OS₂について(M+H)⁺としての実測値：405.0、407.0。 Example 360
N-((4- (4- (N, N-dimethylcarbamimidoyl) phenyl) thiazol-2-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 359. MS: C ₁₈ H ₁₇ For _{ClN 4 OS 2 (M + H} ) + as the measured value: 405.0,407.0.

標題化合物を、実施例359に記載のものと同様の方法により調製した。MS：C₁₉H₁₇ClN₄OS₂について(M+H)⁺としての実測値：417.0、419.0。 Example 361
5-Chloro-N-((4- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) thiazol-2-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 359. MS: C ₁₉ H ₁₇ For _{ClN 4 OS 2 (M + H} ) + as the measured value: 417.0,419.0.

標題化合物を、実施例359に記載のものと同様の方法により調製した。MS：C₂₀H₁₉ClN₄OS₂について(M+H)⁺としての実測値：431.0、433.0。 Example 362
5-Chloro-N-((4- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) thiazol-2-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 359. MS: C ₂₀ H ₁₉ For _{ClN 4 OS 2 (M + H} ) + as the measured value: 431.0,433.0.

標題化合物を、実施例359に記載のものと同様の方法により調製した。MS：C₂₁H₂₁ClN₄OS₂について(M+H)+としての実測値：445.0、447.0。 Example 363
5-Chloro-N-((4- (4- (imino (piperidin-1-yl) methyl) phenyl) thiazol-2-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 359. MS: C ₂₁ H ₂₁ For _{ClN 4 OS 2 (M + H} ) + as the measured value: 445.0,447.0.

Example 364
N-((1- (4- (N, N-dimethylcarbamimidoyl) phenyl) -1H-imidazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide (110)
Scheme 17

Stage 1:
4-Iodobenzonitrile (45, 11.9 g, 52 mmol) and 4-methylimidazole (104, 5.16 g, 62.8 mmol) were dissolved in 100 mL anhydrous dioxane. To this was added trans-1,2-cyclohexanediamine (3.8 mL, 31 mmol), CuI (1.18 mg, 6.2 mmol) and K ₂ CO ₃ (14.7 g, 106 mmol). The mixture was refluxed overnight. This was added to 1000 mL EtOAc, washed with water and brine, dried, concentrated in vacuo and subjected to flash column chromatography to give compound 105 (8.21 g, 86%). MS: for _{C 11 H 9 N 3 (M} + H) + as the measured value: 184.1.

Stage 2:
Compound 105 (1.88 g, 10.3 mmol) was dissolved in 50 mL CCl ₄ . To this was added NBS (7.05 g, 39.6 mmol) and benzoyl peroxide (480 mg, 1.98 mmol). The mixture was refluxed for 3 hours. This was concentrated under reduced pressure and subjected to silica flash chromatography to give compound 106 as the main product (60%). MS: for _{C 11 H 6 Br 3 N 3} (M + H) + as the measured value: 417.8,419.8,421.8.

Stage 3:
Compound 106 (820 mg, 1.95 mmol) was dissolved in 10 mL DMF. To this was added NaN ₃ (240 mg, 3.7 mmol). The mixture was stirred for 3 hours and concentrated in vacuo. The residue was dissolved in 300 mL EtOAc and washed with water and brine. The organic phase was dried and concentrated in vacuo to give compound 107 as a yellow solid (695 mg, 93%).

Stage 4:
Compound 107 (390 mg, 1.02 mmol) was dissolved in 20 mL of methanol. To this was added triethylamine (0.6 mL, 4.1 mmol) and 10% Pd carbon (337 mg). The mixture was stirred for 30 minutes under 10 PSI hydrogen atmosphere. It was then filtered through celite and concentrated in vacuo to give compound 108 as a yellow solid. MS: for _{C 11 H 10 N 4 (M} + H) + as the measured value: 199.1.

Stage 5:
The above crude compound 108 was dissolved in 10 mL DMF. To this was added 5-chlorothiophene-2-carboxylic acid (231 mg, 1.42 mmol), EDC (277 mg, 1.44 mmol), 1-hydroxy-7-azabenzotriazole (HOAt, 17 mg, 0.12 mol) and triethylamine (0.8 mL, 5.7 mmol) was added.

The mixture was stirred at room temperature overnight and diluted with brine. The mixture was extracted 3 times with DCM. The organic phases were combined, dried, concentrated and applied to a flash column to give compound 109 (180 mg, 52% over 2 steps). _{MS: C 16 H 11 ClN 4} OS for (M + H) + as the measured value: 343.0,345.0.

Stage 6:
Performed in the same manner as Example 325, Step 6. MS: C ₁₈ H ₁₈ ClN about ₅ OS (M + H) + as the measured value: 388.1,390.1.

標題化合物を、実施例364に記載のものと同様の方法により調製した。MS：C₁₉H₁₈ClN₅OSについて(M+H)+としての実測値：400.1、402.1。 Example 365
5-Chloro-N-((1- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1H-imidazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 364. MS: C ₁₉ H ₁₈ ClN about ₅ OS (M + H) + as the measured value: 400.1,402.1.

標題化合物を、実施例364に記載のものと同様の方法により調製した。MS：C₁₉H₁₈ClN₅OSについて(M+H)+としての実測値：400.1、402.1。 Example 366
N-((1- (4- (azetidin-1-yl (imino) methyl) phenyl) -1H-imidazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 364. MS: C ₁₉ H ₁₈ ClN about ₅ OS (M + H) + as the measured value: 400.1,402.1.

標題化合物を、実施例364に記載のものと同様の方法により調製した。MS：C₂₀H₂₀ClN₅OSについて(M+H)+としての実測値：414.1、416.1。 Example 367
5-Chloro-N-((1- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1H-imidazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 364. MS: C ₂₀ H ₂₀ ClN about ₅ OS (M + H) + as the measured value: 414.1,416.1.

標題化合物を、実施例364に記載のものと同様の方法により調製した。MS：C₂₁H₂₂ClN₅OSについて(M+H)+としての実測値：428.1、430.1。 Example 368
5-Chloro-N-((1- (4- (imino (piperidin-1-yl) methyl) phenyl) -1H-imidazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 364. MS: C ₂₁ H ₂₂ ClN about ₅ OS (M + H) + as the measured value: 428.1,430.1.

Example 369
N-((5- (4- (N, N-dimethylcarbamimidoyl) phenyl) pyridin-3-yl) methyl) -5-chlorothiophene-2-carboxamide (115)
Scheme 18

Stage 1:
Compound 111 (2.00 g, 10.6 mmol) and triphenylphosphine (3.31 g, 12.6 mmol) were dissolved in 100 mL THF and 50 mL DCM. At 0 ° C., DEAD (3.2 mL, 20 mmol) was added dropwise thereto. After stirring for 2 minutes, DPPA (4.3 mL, 20 mmol) was added. The mixture was stirred overnight (0 ° C. to room temperature). The mixture was diluted with water and extracted 3 times with DCM. The organic phases were combined, dried, concentrated and purified using a flash column to give compound 112 (690 mg, 30%). MS: for _{C 6 H 5 BrN 4 (M} + H) + as the measured value: 213.0,215.0.

Stage 2:
Compound 112 (675 mg, 3.17 mmol) was dissolved in 10 mL THF and 1 mL water. To this was added triphenylphosphine (0.96 g, 3.67 mmol). The mixture was stirred at room temperature for 24 hours. To this was then added EDC (617 mg, 3.22 mmol), 5-chlorothiophene-2-carboxylic acid (502 mg, 3.1 mmol) and HOAt (70 mg, 0.51 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with 2N NaOH and extracted three times with DCM. The organic phases were combined, dried, concentrated and purified using a flash column to give compound 113 (450 mg, 43%). MS: C ₁₁ H ₈ BrClN about ₂ OS (M + H) + as the measured value: 331.0,333.0.

Stage 3:
Compound 113 (450 mg, 1.35 mmol), 4-cyanobenzeneboronic acid (282 mg, 1.92 mmol), Pd (Ph ₃ P) ₄ (130 mg, 0.11 mmol), K ₂ CO ₃ (596 mg, 5 mL diglyme and 5 mL water) 4.31 mmol) was degassed for 5 minutes using a stream of argon. The mixture was then stirred in an 80 ° C. bath overnight. The mixture was poured into water and extracted 3 times with DCM. The organic phases were combined, dried, concentrated and purified using a flash column to give compound 114 (350 mg, 73%). _{MS: C 18 H 12 ClN 3} OS for (M + H) + as the measured value: 354.0,356.0.

Stage 4:
Performed in the same manner as Example 325, Step 6. _{MS: C 20 H 19 ClN 4} OS for (M + H) + as the measured value: 339.1,401.1.

標題化合物を、実施例369に記載のものと同様の方法により調製した。MS：C₂₁H₁₉ClN₄OSについて(M+H)+としての実測値：411.1、413.1。 Example 370
5-Chloro-N-((5- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) pyridin-3-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 369. _{MS: C 21 H 19 ClN 4} OS for (M + H) + as the measured value: 411.1,413.1.

標題化合物を、実施例369に記載のものと同様の方法により調製した。MS：C₂₁H₁₉ClN₄OSについて(M+H)+としての実測値：411.1、413.1。 Example 371
N-((5- (4- (azetidin-1-yl (imino) methyl) phenyl) pyridin-3-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 369. _{MS: C 21 H 19 ClN 4} OS for (M + H) + as the measured value: 411.1,413.1.

標題化合物を、実施例369に記載のものと同様の方法により調製した。MS：C₂₂H₂₁ClN₄OSについて(M+H)+としての実測値：425.1、427.1。 Example 372
5-Chloro-N-((5- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) pyridin-3-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 369. _{MS: C 22 H 21 ClN 4} OS for (M + H) + as the measured value: 425.1,427.1.

標題化合物を、実施例369に記載のものと同様の方法により調製した。MS：C₂₃H₂₃ClN₄OSについて(M+H)+としての実測値：439.1、441.1。 Example 373
5-Chloro-N-((5- (4- (imino (piperidin-1-yl) methyl) phenyl) pyridin-3-yl) methyl) thiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 369. _{MS: C 23 H 23 ClN 4} OS for (M + H) + as the measured value: 439.1,441.1.

Example 374
N-((5- (4- (N, N-dimethylcarbamimidoyl) phenyl) -2-fluorophenyl) methyl) -5-chlorothiophene-2-carboxamide (119)
Scheme 19

Stage 1:
Compound 116 hydrochloride (490 mmol, 2.04 mmol), 5-chlorothiophene-2-carboxylic acid (390 mg, 2.40 mmol) and triethylamine (0.35 mL, 2.51 mmol) were dissolved in 20 mL DCM. To this was added DMAP (25 mg) and EDC (450 mg, 2.35 mmol). The mixture was stirred overnight. This was diluted with DCM, washed with water, dried, concentrated and purified using a flash column to give compound 117 (90%). MS: C ₁₂ H ₈ BrClFNOS for (M + H) + as the measured value: 348.0,350.0.

Stage 2:
Performed in the same manner as Example 369, Step 3. MS: C ₁₉ H ₁₂ ClFN about ₂ OS (M + H) + as the measured value: 371.0,373.0.

Stage 3:
Performed in the same manner as Example 369, Step 4. _{MS: C 21 H 19 ClFN 3} OS for (M + H) + as the measured value: 416.1,418.1.

標題化合物を、実施例374に記載のものと同様の方法により調製した。MS：C₂₂H₁₉ClFN₃OSについて(M+H)+としての実測値：428.1、430.1。 Example 375
5-chloro-N-((5- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -2-fluorophenyl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 374. _{MS: C 22 H 19 ClFN 3} OS for (M + H) + as the measured value: 428.1,430.1.

標題化合物を、実施例374に記載のものと同様の方法により調製した。MS：C₂₃H₂₁ClFN₃OSについて(M+H)+としての実測値：442.1、444.1。 Example 376
5-chloro-N-((5- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -2-fluorophenyl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 374. _{MS: C 23 H 21 ClFN 3} OS for (M + H) + as the measured value: 442.1,444.1.

標題化合物を、実施例374に記載のものと同様の方法により調製した。MS：C₂₁H₁₉ClFN₃OSについて(M+H)+としての実測値：416.1、418.1。 Example 377
N-((3- (4- (N, N-dimethylcarbamimidoyl) phenyl) -4-fluorophenyl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 374. _{MS: C 21 H 19 ClFN 3} OS for (M + H) + as the measured value: 416.1,418.1.

標題化合物を、実施例374に記載のものと同様の方法により調製した。MS：C₂₂H₁₉ClFN₃OSについて(M+H)+としての実測値：428.1、430.1。 Example 378
5-Chloro-N-((3- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -4-fluorophenyl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 374. _{MS: C 22 H 19 ClFN 3} OS for (M + H) + as the measured value: 428.1,430.1.

標題化合物を、実施例374に記載のものと同様の方法により調製した。MS：C₂₃H₂₁ClFN₃OSについて(M+H)+としての実測値：442.1、444.1。 Example 379
5-chloro-N-((3- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -4-fluorophenyl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 374. _{MS: C 23 H 21 ClFN 3} OS for (M + H) + as the measured value: 442.1,444.1.

標題化合物を、実施例374に記載のものと同様の方法により調製した。MS：C₂₁H₂₀ClN₃OSについて(M+H)+としての実測値：398.1、400.1。 Example 380
N-((3- (4- (N, N-dimethylcarbamimidoyl) phenyl) phenyl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 374. _{MS: C 21 H 20 ClN 3} OS for (M + H) + as the measured value: 398.1,400.1.

標題化合物を、実施例374に記載のものと同様の方法により調製した。MS：C₂₂H₂₀ClN₃OSについて(M+H)+としての実測値：410.1、412.1。 Example 381
5-Chloro-N-((3- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) phenyl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 374. _{MS: C 22 H 20 ClN 3} OS for (M + H) + as the measured value: 410.1,412.1.

標題化合物を、実施例374に記載のものと同様の方法により調製した。MS：C₂₃H₂₂ClN₃OSについて(M+H)+としての実測値：424.1、426.1。 Example 382
5-Chloro-N-((3- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) phenyl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 374. _{MS: C 23 H 22 ClN 3} OS for (M + H) + as the measured value: 424.1,426.1.

Example 383
5-Chloro-N-((1- (6- (4-methyl-1,4-diazepan-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl Thiophene-2-carboxamide (123)
Scheme 20

Stage 1:
5-Amino-2-chloropyridine (120, 4.91 g, 38.3 mmol) was dissolved in 15 mL TFA. To this was added NaNO ₂ (2.91 g, 42.2 mmol) in small portions in an ice bath. The mixture was stirred in the cooling bath for 30 minutes. To this was then added an ice cold solution of NaN ₃ (2.50 g, 38.3 mmol in 10 mL water). The mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure and diluted with 400 mL of chloroform. This was washed 3 times with water, dried, concentrated and purified by flash column to give compound 121 (3.46 g, 59%). MS: for _{C 5 H 3 ClN 4 (M} + H) + as the measured value: 155.0,157.0.

Stage 2:
Azidopyridine 121 (3.46 g, 22.5 mmol) and alkyne 34 (see Scheme 5 in Example 291; 4.38 g, 22.0 mmol) were refluxed in 10 mL toluene and 15 mL DMF for 7 hours. The reaction was not yet complete. The mixture was concentrated and applied to a flash column to isolate the main product 1,4-disubstituted triazole 122 as a white solid (3.19 g, 40%). MS: C ₁₃ H ₉ Cl for ₂ N5OS (M + H) + as the measured value: 354.0,356.0. The by-product 1,5-triazole isomer was isolated in 7% yield (0.56 g).

Stage 3:
In a sealed tube, a mixture of compound 122 (50 mg, 0.14 mmol), N-methylhomopiperazine (53 μL, 0.42 mmol) and Cs ₂ CO ₃ (91 mg, 0.28 mmol) in DMSO (1 mL) in a 120 ° C. bath. For 2 hours. The mixture was directly subjected to preparative reverse phase HPLC to give the title compound as a white powder after lyophilization. _{MS: C 19 H 22 ClN 7} OS for (M + H) + as the measured value: 432.1,434.1.

標題化合物を、実施例383に記載のものと同様の方法により調製した。MS：C₁₈H₂₀ClN₇OSについて(M+H)+としての実測値：418.1、420.1。 Example 384
N-((1- (6- (1,4-diazepan-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2 -Carboxamide

The title compound was prepared in a similar manner as described in Example 383. _{MS: C 18 H 20 ClN 7} OS for (M + H) + as the measured value: 418.1,420.1.

標題化合物を、実施例383に記載のものと同様の方法により調製した。MS：C₁₈H₁₉ClN₆O₂Sについて(M+H)+としての実測値：419.1、421.1。 Example 385
N-((1- (6- (1,4-Oxazepan-4-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2 -Carboxamide

The title compound was prepared in a similar manner as described in Example 383. MS: C ₁₈ H ₁₉ ClN about _{6 O 2 S (M + H} ) + as the measured value: 419.1,421.1.

標題化合物を、実施例383に記載のものと同様の方法により調製した。MS：C₁₇H₁₇ClN₆O₂Sについて(M+H)+としての実測値：405.1、407.1。 Example 386
5-Chloro-N-((1- (6-morpholinopyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 383. MS: C ₁₇ H ₁₇ ClN about _{6 O 2 S (M + H} ) + as the measured value: 405.1,407.1.

標題化合物を、実施例383に記載のものと同様の方法により調製した。MS：C₁₇H₁₅ClN₆O₃Sについて(M+H)+としての実測値：419.1、421.1。 Example 387
5-Chloro-N-((1- (6- (3-oxomorpholino) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 383. _{MS: C 17 H 15 ClN 6} O 3 for S (M + H) + as the measured value: 419.1,421.1.

標題化合物を、実施例383に記載のものと同様の方法により調製した。MS：C₁₈H₁₇ClN₆O₂Sについて(M+H)+としての実測値：417.1、419.1。 Example 388
5-Chloro-N-((1- (6- (2-oxopiperidin-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophen-2- Carboxamide

The title compound was prepared in a similar manner as described in Example 383. MS: C ₁₈ H ₁₇ ClN about _{6 O 2 S (M + H} ) + as the measured value: 417.1,419.1.

標題化合物を、実施例383に記載のものと同様の方法により調製した。MS：C₁₈H₁₃ClN₆O₂Sについて(M+H)+としての実測値：413.0、415.0。 Example 389
5-Chloro-N-((1- (6- (2-oxopyridin-1 (2H) -yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene -2-carboxamide

The title compound was prepared in a similar manner as described in Example 383. MS: C ₁₈ H ₁₃ ClN about _{6 O 2 S (M + H} ) + as the measured value: 413.0,415.0.

標題化合物を、実施例383に記載のものと同様の方法により調製した。MS：C₁₇H₁₈ClN₇OSについて(M+H)+としての実測値：404.1、406.1。 Example 390
5-Chloro-N-((1- (6- (piperazin-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 383. MS: C ₁₇ H ₁₈ For _{ClN 7 OS (M + H)} + as the measured value: 404.1,406.1.

標題化合物を、実施例383に記載のものと同様の方法により調製した。MS：C₁₈H₂₀ClN₇OSについて(M+H)+としての実測値：418.1、420.1。 Example 391
5-Chloro-N-((1- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophen-2- Carboxamide

The title compound was prepared in a similar manner as described in Example 383. _{MS: C 18 H 20 ClN 7} OS for (M + H) + as the measured value: 418.1,420.1.

標題化合物を、実施例383に記載のものと同様の方法により調製した。MS：C₁₈H₁₉ClN₆OSについて(M+H)+としての実測値：403.1、405.1。 Example 392
5-Chloro-N-((1- (6- (piperidin-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 383. MS: C ₁₈ H ₁₉ ClN about ₆ OS (M + H) + as the measured value: 403.1,405.1.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₅H₁₈ClF₃N₄O₂Sについて(M+H)⁺としての実測値：531.0、533.0。 Example 393
5-chloro-N-((3- (4- (8- (trifluoromethyl) quinolin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 25 H 18 ClF 3} N 4 O 2 for S (M ⁺ H) + as the measured value: 531.0,533.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₅H₁₈ClF₃N₄O₂Sについて(M+H)⁺としての実測値：531.0、533.0。 Example 394
5-chloro-N-((3- (4- (7- (trifluoromethyl) quinolin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 25 H 18 ClF 3} N 4 O 2 for S (M ⁺ H) + as the measured value: 531.0,533.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₅H₁₈ClF₃N₄O₂Sについて(M+H)⁺としての実測値：531.0、533.0。 Example 395
5-chloro-N-((3- (4- (6- (trifluoromethyl) quinolin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 25 H 18 ClF 3} N 4 O 2 for S (M ⁺ H) + as the measured value: 531.0,533.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₄H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：463.1、465.1。 Example 396
5-Chloro-N-((3- (4- (quinolin-6-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 24 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 463.1,465.1.

標題化合物を、実施例162に記載のものと同様の方法により調製した。MS：C₂₀H₁₈ClN₃O₃Sについて(M+H)⁺としての実測値：416.0、418.0。 Example 397
5-chloro-N-((3- (4- (2,5-dihydro-1H-pyrrol-1-carbonyl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2- Carboxamide

The title compound was prepared by a method similar to that described in Example 162. _{MS: C 20 H 18 ClN 3} O 3 for S (M ⁺ H) + as the measured value: 416.0,418.0.

標題化合物を、実施例162に記載のものと同様の方法により調製した。MS：C₂₂H₂₄ClN₃O₄Sについて(M+H)⁺としての実測値：462.0、464.0。 Example 398
5-chloro-N-((3- (4- (2,5-dihydro-1H-pyrrol-1-carbonyl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2- Carboxamide

The title compound was prepared by a method similar to that described in Example 162. _{MS: C 22 H 24 ClN 3} O 4 for S (M ⁺ H) + as the measured value: 462.0,464.0.

標題化合物を、実施例162に記載のものと同様の方法により調製した。MS：C₁₉H₂₀ClN₃O₄Sについて(M+H)⁺としての実測値：422.0、424.0。 Example 399
N-((3- (4-((2-hydroxypropyl) carbamoyl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) -5-chlorothiophene-2-carboxamide

The title compound was prepared by a method similar to that described in Example 162. _{MS: C 19 H 20 ClN 3} O 4 for S (M ⁺ H) + as the measured value: 422.0,424.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₁H₁₉ClN₄O₂Sについて(M+H)⁺としての実測値：427.0、429.0。 Example 400
5-Chloro-N-((3- (4- (3-methylpyridin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 21 H 19 ClN 4} O 2 for S (M ⁺ H) + as the measured value: 427.0,429.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₂H₂₁ClN₄O₃Sについて(M+H)⁺としての実測値：457.1、459.1。 Example 401
5-chloro-N-((3- (4- (2-ethoxypyridin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 22 H 21 ClN 4} O 3 for S (M ⁺ H) + as the measured value: 457.1,459.1.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₀H₁₅Cl₃N₄O₂Sについて(M+H)⁺としての実測値：481.0、483.0。 Example 402
5-chloro-N-((3- (4- (3,5-dichloropyridin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 20 H 15 Cl 3} N for _{4 O 2 S (M + H} ) + as the measured value: 481.0,483.0.

標題化合物を、実施例222に記載のものと同様の方法により調製した。MS：C₂₁H₁₆ClF₃N₄O₂Sについて(M+H)⁺としての実測値：481.1、483.1。 Example 403
5-chloro-N-((3- (4- (3- (trifluoromethyl) pyridin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide

The title compound was prepared in a similar manner as described in Example 222. _{MS: C 21 H 16 ClF 3} N 4 O 2 for S (M ⁺ H) + as the measured value: 481.1,483.1.

Example 404
This example shows how to evaluate the compounds of the invention, as well as the results obtained with such assays. The in vitro and in vivo factor Xa isoform activity of the compounds of the invention can be determined by various methods known in the art, such as testing for the ability to inhibit the activity of the factor Xa isoform. The strong affinity for factor Xa exhibited by the compounds of the present invention can be measured by the IC ₅₀ value (nM). The IC ₅₀ value is the concentration of compound (nM) required to provide 50% inhibition of the factor Xa isoform. The smaller the IC ₅₀ value, the more active (strong) the compound is at inhibiting the factor Xa isoform.

In vitro assays for detecting and measuring inhibitory activity against factor Xa are as follows:
IC ₅₀ and Ki measurements
Substrate:
Substrate S-2765 (ZD-Arg-Gly-Arg-pNA.HCl) was obtained from Diapharma (West Chester, OH).

enzyme:
Human plasma protein factor Xa was purchased from Haematologic Technologies (Essex Junction, VT).

Method
IC ₅₀ measurements All assays are performed in 96-well microtiter plates and the proteolytic activity of the enzyme (factor Xa) is measured by following the cleavage of the paranitroanilide substrate. The assay buffer used for the proteolytic assay was Tris-buffered saline (20 mM Tris, 150 mM NaCl, 5 mM CaCl ₂ , 0.1% bovine serum albumin (BSA), 5% dimethyl sulfoxide (DMSO) pH 7.4). Inhibitors were serially diluted in 96-well microtiter plates to obtain concentrations ranging from 0.01 nM to 10 μM (final). Duplicate wells were assayed and control wells without inhibitor were included. Enzyme was added to each well (fXa concentration = 1 nM) and the plate was shaken for 5 seconds and then incubated at room temperature for 5 minutes. S2765 was added (final 100 μM) and the plate was shaken for 5 seconds (final volume in each well was 200 μl). The extent of substrate hydrolysis was measured for 2 minutes at 405 nm on a Thermomax plate reader (Molecular Devices, Sunnyvale, Calif.). In each inhibitor concentration range, the initial velocity (mOD / min) was applied to a 4-parameter equation using Softmax data analysis software. Parameter C derived from the curve fit obtained corresponded to a 50% maximum inhibitory concentration (IC ₅₀ ).

上式で、[S]は基質濃度(200μM)であり、K_mはS2765のミハエリス定数である。 K _i measurement The assay buffer for this series of assays was Hepes buffered saline (20 mM Hepes, 150 mM NaCl, 5 mM CaCl ₂ , 0.1% PEG-8000, pH 7.4). Inhibitors were serially diluted in duplicate wells in 96-well microtiter plates to obtain final concentrations ranging from 5 pM to a final 3 μM. A control without inhibitor (8 wells) was included. Enzyme, fXa (final 1 nM) was added to the wells. Substrate S-2765 (final 200 μM) was added and the extent of substrate hydrolysis was measured on a Thermomax plate reader at 405 nm for 5 minutes using Softmax software. Initial velocity (mOD / min) was analyzed by nonlinear least square regression with Plate Ki software (BioKin Ltd, Pullman, WA) (references: Kusmic P, Sideris S, Cregar LM, Elrod KC, Rice KD, Janc J. High) -throughput screening of enzyme inhibitors: Automatic determination of tight-binding inhibition constants. Anal. Biochemistry 2000, 281: 62-67). The model used to fit the inhibitor dose response curve was the Morrison equation. It was determined the apparent K _i (Ki ^*). Total _Ki was calculated using the following formula:

In the above formula, [S] is the substrate concentration (200 μM), and K _m is the Michaelis constant of S2765.

hERG (human ether-a-go-go related gene protein) membrane binding assay
Human embryonic kidney (HEK293) cells stably transfected with hERG cDNA were used for membrane preparation (reference: Zhou, Z., Gong, Q., Ye, B., Fan, Z., Makielski , C., Robertson, G., January, CT., Properties of HERG stably expressed in HEK293 cells studied at physiological temperature. Biophys. J, 1998, 74: 230-241). The assay buffer was 50 mM Tris, 10 mM KCl, 1 mM MgCl ₂ , pH 7.4. A competition assay for hERG binding was performed in 96-well plates containing 50 μL of ³ H-dofetilide at a concentration of 3.5 nM (final concentration 0.01% ethanol). Test compounds were added at final concentrations of 100 μM, 33.33 μM, 11.11 μM, 3.70 μM, 1.23 μM, 0.41 μM, 0.14 μM, 0.046 μM, 0.015 μM, and 0.005 μM (1.0% DMSO). Each compound was tested in duplicate on each of two plates. Total binding was quantified by adding 50 μL of assay buffer instead of compound. Nonspecific binding was quantified by adding 50 μL of 50 μM terfenadine instead of the test compound. All assays were started by adding 150 μL of membrane homogenate (final concentration of 15 ug / well of protein) to the well (total volume = 250 μL / well) and incubating the plates on a shaking platform for 80 minutes at room temperature. All assays were stopped by vacuum filtration through glass fiber filters followed by two washes with cold assay buffer. The filter plate was dried at 55 ° C. for 90 minutes, after which Microscint 0 (50 μL) was added to each well of the dried filter plate. Plates were counted using a 1 minute protocol on a Packard Topcount (Perkin Elmer, Boston, Mass.). Using Packard Topcount scintillation readings (counts per minute, CPM) data, calculate percent inhibition of ³ H-dofetilide binding using total binding control values corrected for non-specific binding for each compound at each concentration did. IC ₅₀ values were calculated from percent inhibition curves generated using Excel XL Fit software (Microsoft). The equilibrium dissociation constant (K _i ) was calculated using the formula of Cheng and Prusoff (“Relationship between the inhibition constant (K _i ) and the concentration of inhibitor which causes 50 per cent inhibition (I ₅₀ ) of an enzymatic reaction, "See Biochem Pharmacol., 1973, 22 (23); 3099-108.
K _i = IC ₅₀ / [1 + ([L] / K _D ).

A compound can be tested by this assay and its corresponding IC ₅₀ inhibition value can be calculated from the assay data.

The following examples showed Factor Xa IC ₅₀ values of 100 nM or less:
7-10, 16-18, 20-32, 48-51, 56-65, 67, 69-72, 77, 82, 86, 91-142, 161-164, 166, 193-200, 203-205, 208,209,216-219,225-227,239,240,242,243,245-248,253,254,269,278-286,289-303,305-341,352,364-377,379- 384, 387-389, 394, 395, 397, 400, 401, 403.

The following examples showed Factor Xa IC ₅₀ values greater than 100 nM and less than 500 nM:
11-15, 33, 66, 68, 73-76, 78-80, 83-85, 87-90, 165, 167, 186-190, 206, 210, 211, 229, 230, 233, 235, 237, 238, 241, 244, 342-347, 349-351, 353, 354, 359, 378, 385, 386, 390-392, 398.

The following examples showed Factor Xa IC ₅₀ values of 500 nM and above:
1, 4, 5, 34-47, 52-55, 81, 143-160, 168-181, 183-185, 191, 192, 201, 202, 207, 212-215, 220-224, 228, 231, 232, 234, 236, 249-252, 255-268, 270-276, 288, 304, 348, 355-358, 360-363, 393, 396, 399, 402.

  The present invention provides several aspects. It will be apparent that the examples may be modified to provide other aspects of the invention. Therefore, it will be understood that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been shown by way of example.

Claims (32)

A compound having the following formula:

Or a pharmaceutically acceptable salt thereof, wherein A is halogen, R ^A , —OR ^A , N (R ^A ) ₂ , CO ₂ R ^A , CON (R ^A ) ₂ , S (O) _{0 selected from 2} R ^A , S (O) ₂ N (R ^A ) ₂ , X ¹ OR ^A , X ¹ CO ₂ R ^A , X ¹ CON (R ^A ) ₂ , X ¹ N (R ^A ) ₂ Pyridine, pyrimidine, pyrazine, piperidine, morpholine, piperazine, isoxazole, isothiazole, pyrazole, imidazole, oxazole, thiazole, isoxazoline, pyrazoline, imidazoline, 1,2,3-triazole, 2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, pylori Represents a group selected from gin, pyrrole, furan and thiophene , wherein R ^A is each independently selected from H, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl; Or two R ^A optionally attached to the same atom combine to form a 3-, 4-, 5-, 6- or 7-membered ring;
R is a member selected from the group consisting of H and C _1-4 alkyl;
R ¹ is a member selected from the group consisting of halogen, C _1-8 alkyl, C _2-8 alkenyl and C _2-8 alkynyl;
R ² is selected from the group consisting of H, C _1-8 alkyl, —X—OR ^2a , —X—SR ^2a , —X—COR ^2a , —X—CO ₂ R ^2a and —XN (R ^2a ) _2. Wherein X is C _1-8 alkylene, and each R ^2a is independently selected from the group consisting of H and C _1-8 alkyl, or optionally on the same nitrogen atom. Two attached R ^2a groups combine to form a 4-, 5-, 6- or 7-membered ring;
W is

A member selected from the group consisting of
Wherein Z ¹ , Z ² , and Z ³ are each independently N, C, or CH, and ^{two of} Z ¹ , Z ² , and Z ³ are other than N;
Subscript n is an integer from 0 to 3 and subscript m is an integer from 0 to 1;
R ⁴ is halogen, —OR ^4a , —OC (O) R ^4a , —NR ^4a R ^4b , —SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R ^4b , —R ^4c , —CN, —NO ₂ , —CO ₂ R ^4a , —CONR ^4a R ^4b , —C (O) R ^4a , —OC (O) NR ^4a R ^4b , —NR ^4b C (O _{^{) R 4a, -NR 4b C (}} O) 2 R 4c, -NR 4a -C (O) NR 4a R 4b, -X 1 OR 4a, -X 1 OC (O) R 4a, -X 1 NR 4a R ^{4b, -X 1 SR 4a, -X} 1 S (O) R 4a, -X 1 S (O) 2 R 4a, -X 1 CN, -X 1 NO 2, -X 1 CO 2 R 4a, -O -X ¹ CO ₂ R ^4a , -X ¹ CONR ^4a R ^4b , -O-X ¹ CONR ^4a R ^4b -X ¹ C (O) R ^4a , -O-X ¹ NR ^4a R ^4b , -S (O) X ¹ NR ^4a R ^4b , -S (O) ₂ X ¹ NR ^4a R ^4b , -X ¹ OC (O) NR ^4a R ^4b , -X ¹ NR ^4a C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a C (O) NR ^4a R ^4b , -Y, A member selected from the group consisting of —X ¹ —Y, —O—Y, —NR ^4a Y, —SY, —S (O) Y and —S (O) ₂ Y;
R ^{4 ′} is —C (═NH) R ^4a , —C (═NR ^4c ) R ^4a , —C (═NH) NR ^4a R ^4b , —C (= NR ^4c ) NR ^4a R ^4b , —C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b , -X ² -C (= NH) NR ^4a R ^4b , -X ² -C (= NR ^4c ) NR ^4a R ^4b , -X ² -C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b and -C (= NR ^4a ) NR ^4a -Y is a member selected from the group consisting of:
Where Y is halogen, ^{oxo, -OR 4a, -OC (O)} R 4a, -NR 4a R 4b, -R 4c, -SR 4a, S (O) R 4a, S (O) 2 R 4a, S _{^{(O) 2 NR 4a R 4b}} , -CN, -NO 2, -CO 2 R 4a, -CONR 4a R 4b, -C (O) R 4a, -NR 4b C (O) R 4a, -NR 4b C _{^{(O) 2 R 4c, -X}} 1 R 4a, -X 1 OR 4a, -X 1 SR 4a, -X 1 S (O) R 4a, -X 1 S (O) 2 R 4a, -X 1 CN _{^{, -X 1 NO 2, -X 1}} CO 2 R 4a, -X 1 CONR 4a R 4b, -X 1 C (O) R 4a, -O-X 1 NR 4a R 4b, -S (O) X 1 _{^{NR 4a R 4b, -S (O}} ) 2 X 1 NR 4a R 4b, -X 1 OC (O) NR 4a R ^{b, -X 1 NR 4b C (} O) R 4a, -X 1 NR 4b C (O) 2 R 4c, -X 1 NR 4a -C (O) NR 4a R 4b, -X 1 OC (O) R ^{4a, -X 1 NR 4a R 4b} , -O-X 1 OR 4a, -O-X 1 NR 4a R 4b, -O-X 1 CO 2 R 4a, -O-X 1 CONR 4a R 4b, -NR ^{4b -X 1 oR 4a, -NR 4b} -X 1 NR 4a R 4b, -NR 4b -X 1 CO 2 R 4a, and ^-NR 4b ^-X 1 ^CONR 4a ^1~3 selected from the group consisting of ^{R 4b} 5- or 6-membered aryl, heterocyclyl or aryl-C _1-2 alkyl, optionally substituted by 1 substituent,
X ¹ and X ² are each a member independently selected from the group consisting of C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene;
R ^4a and R ^4b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl Independently selected from the group consisting of:, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
R ^4c is C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl, respectively. Independently selected from the group consisting of —C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
Optionally any two of R ^4a , R ^4b and R ^4c , when part of a common R ⁴ or R ^{4 ′} substituent, combine with 0 to 2 atoms each bonded to Can form a saturated or unsaturated, 4-9 membered monocyclic or bicyclic ring having as an additional heteroatom as a ring member;
R ^4a , R ^4b, and R ^4c are —OH, oxo, —R ^m , —OR ^m , —OC (O) NHR ^m , —OC (O) N (R ^m ) ₂ , —SH, —SR ^{m, respectively. _{-S (O) R m, -S}} (O) 2 R m, -SO 2 NH 2, -S (O) 2 NHR m, -S (O) 2 N (R m) 2, -NHS (O) _{^{2 R m, -NR m S (}} O) 2 R m, -C (O) NH 2, -C (O) NHR m, -C (O) N (R m) 2, -C (O) R m , —NHC (O) R ^m , —NR ^m C (O) R ^m , —NHC (O) NH ₂ , —NR ^m C (O) NH ₂ , —NR ^m C (O) NHR ^m , —NHC ( _{^{O) NHR m, -NR m C}} (O) N (R m) 2, -NHC (O) N (R m) 2, -CO 2 H, -CO 2 R m, -NHCO 2 R m, -NR _{^{m CO 2 R m, -CN,}} -NO 2, -NH 2, from _{^{-NHR m, -N (R m)}} 2, -NR m S (O) NH 2 and _{^{-NR m S (O) 2 NHR}} m May be further substituted with 1 to 3 members selected from the group consisting of wherein R ^m is each independently unsubstituted C _1-6 alkyl, benzyl, or an atom to which each is attached. In combination to form a saturated 4, 5, 6 or 7 membered ring having 0 to 2 additional heteroatoms as ring members;
R ⁵ is —R ^5a , —CO ₂ R ^5c , —CONR ^5a R ^5b , —C (O) R ^5a , —C (═NR ^5a ) NR ^5a R ^5b , —C (= N ⁺ R ^5c R ^5c ) ^{NR 5a R 5b, -C (=} NR 5a) R 5a, -C (= NR 5a) Y 1, -X 3 OR 5a, -X 3 OC (O) R 5a, -X 3 NR 5a R 5b, - ^{X 3 SR 5a, -X 3 CN} , -X 3 NO 2, -X 3 CO 2 R 5a, -X 3 CONR 5a R 5b, -X 3 C (O) R 5a, -X 3 OC (O) NR ^5a R ^5b , -X ³ NR ^5a C (O) R ^5a , -X ³ NR ^5b C (O) ₂ R ^5c , -X ³ NR ^5a C (O) NR ^5a R ^5b , -X ³ -C (= NR ^5a ) selected from the group consisting of NR ^5a R ^5b , -Y ¹ , and -X ³ -Y ¹ A member
Wherein Y ¹ is ^{halogen, -OR 5a, -OC (O)} R 5a, -NR 5a R 5b, -R 5c, -SR 5a, -CN, -NO 2, -CO 2 R 5a, -CONR 5a R ^{5b, -C (O) R 5a} , -NR 5b C (O) R 5a, -NR 5b C (O) 2 R 5C, -X 3 OR 5a, -X 3 SR 5a, -X 3 CN, -X _{^{3 NO 2, -X 3 CO 2}} R 5a, -X 3 CONR 5a R 5b, -X 3 C (O) R 5a, -X 3 OC (O) NR 5a R 5b, -X 3 NR 5b C (O _{^{) R 5a, -X 3 NR 5b}} C (O) 2 R 5c, -X 3 NR 5a -C (O) NR 5a R 5b, -X 3 OC (O) R 5a, -X 3 NR 5a R 5b, ^{-O-X 3 OR 5a, -O} -X 3 NR 5a R 5b, -O-X 3 CO ^{R 5a, -O-X 3 CONR} 5a R 5b, -NR 5b -X 3 OR 5a, -NR 5b -X 3 NR 5a R 5b, -NR 5b -X 3 CO 2 R 5a, and ^-NR 5b -X ³ CONR ^5a R ^5b is a 5- or 6-membered aryl or heteroaryl ring or aryl-C _1-2 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of:
Each X ³ is a member independently selected from the group consisting of C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene;
R ^5a and R ^5b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl Independently selected from the group consisting of:, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
R ^5c is C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl, respectively. Independently selected from the group consisting of —C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
Optionally, any two of R ^5a , R ^5b and R ^5c , when part of a common R ⁵ substituent, combine with the atom to which each is attached to form 0 to 1 additional hetero Can form saturated 4, 5, 6 or 7 membered rings having atoms as ring members;
R ^5a , R ^5b and R ^5c are —OH, —OR ⁿ , —OC (O) NHR ⁿ , —OC (O) N (R ⁿ ) ₂ , —SH, —SR ⁿ —S (O) R, respectively. _{^{n, -S (O) 2 R}} n, -SO 2 NH 2, -S (O) 2 NHR n, -S (O) 2 n (R n) 2, -NHS (O) 2 R n, -NR _{^{n S (O) 2 R n}} , -C (O) NH 2, -C (O) NHR n, -C (O) n (R n) 2, -C (O) R n, -NHC (O) _{^{R n, -NR n C (O}} ) R n, -NHC (O) NH 2, -NR n C (O) NH 2, -NR n C (O) NHR n, -NHC (O) NHR n, - _{^{NR n C (O) n (}} R n) 2, -NHC (O) n (R n) 2, -CO 2 H, -CO 2 R n, -NHCO 2 R n, -NR n CO 2 R n _-CN, is selected from the group consisting of _{^{-NO 2, -NH 2, -NHR n}} , -N (R n) 2, -NR n S (O) NH 2 and _{^{-NR n S (O) 2 NHR}} n It may be further substituted with 1 to 3 members, where each R ⁿ is independently unsubstituted C _1-6 alkyl or benzyl; and the wavy line indicates the point of attachment to the rest of the molecule. W is (a), (d), (e) and (c):

The compound of claim 1 having a formula selected from the group consisting of:   3. A compound according to claim 1 or 2, wherein W has the formula selected from the group consisting of (a), (d) and (e).   3. A compound according to claim 1 or 2, wherein W has the formula (c). m is 1 and R ^{4 ′} is

5. A compound according to any one of claims 1 to 4 wherein the compound is selected from the group consisting of; and the wavy line indicates the point of attachment to the rest of the molecule. n is 1 and R ⁴ are C ^androgenic, OR _{4a, C 1-4 ^{alkyl, SR 4a, S (O)}} R 4a, S (O) 2 R 4a, S (O) 2 N (R 4a R ^4b ), NR ^4a R ^4b , C _1-4 alkyl OR ^4a , C _1-4 alkyl NR ^4a R ^4b , C _1-4 alkyl CO ₂ R ^4a , OC _1-4 alkyl OR ^4a , OC _1-4 alkyl ^{N (R 4a N 4b),} N (R 4a) C 1-4 alkyl _{^{OR 4b, N (R 4a)}} C 1-4 alkyl _{^{N (R 4a R 4b),}} S (O) 2 C 1-4 alkyl N (R ^4a R ^4b ),

Independently selected from the group consisting of: R ^4a is each independently H or C _1-4 alkyl; R ^{4 b} is H, OH, NH ₂ , N (CH ₃ ) ₂ , CONH ₂ and CON ( CH ₃₎ are independently selected from the group consisting of _2; and the wavy line indicates the point of attachment to the rest of the molecule, the compounds of any one of claims 1 to 4. n is 1 and R ⁴ is

5. A compound according to any one of claims 1 to 4, wherein the compound is selected from the group consisting of: and the wavy line indicates the point of attachment to the rest of the molecule. The compound according to any one of claims 1 to 7, wherein R ^{4 '} is bonded to the ring at a position para to A. R ⁴ is attached to the ring at a position ortho to A, compound of any one of claims 1-8.   10. A compound according to any one of claims 1 to 9, wherein Y is an optionally substituted member selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl, pyrazolyl, triazolyl and imidazolyl. A is peak lysine, pyrimidine, pyrazine, pin Perijin is a member selected from the group consisting of morpholine and piperazine compound of any one of claims 1-10. A is

Selected from the group consisting of:
n is an integer from 0 to 3; R ³ is halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, OR ^3a , N (R ^3a ) ₂ , X ⁰ CO ₂ R, respectively. ^{3 a} , X ⁰ CON (R ^3a ) ₂ , SO ₂ C _1-4 alkyl , SO ₂ N (R ^3a ) ₂ ; independently selected from the group consisting of R ^3a , H, C _1-8 alkyl, C Independently selected from the group consisting of _2-8 alkenyl and C _2-8 alkynyl; and X ⁰ is a bond or C _1-8 alkylene; and the dashed line indicates the point of attachment to A and the wavy line indicates the remainder of the molecule 11. A compound according to any one of claims 1 to 10 which exhibits a point of attachment to. Having the formula, according to claim 1 Symbol placement compounds:

Or a pharmaceutically acceptable salt thereof, wherein R is a member selected from the group consisting of H and C _1-4 alkyl;
R ¹ is a member selected from the group consisting of halogen, C _1-8 alkyl, C _2-8 alkenyl and C _2-8 alkynyl;
R ² is selected from the group consisting of H, C _1-8 alkyl, —X—OR ^2a , —X—SR ^2a , —X—COR ^2a , —X—CO ₂ R ^2a and —XN (R ^2a ) _2. Wherein X is C _1-8 alkylene, and each R ^2a is independently selected from the group consisting of H and C _1-8 alkyl, or optionally on the same nitrogen atom. Two attached R ^2a groups combine to form a 4-, 5-, 6- or 7-membered ring;
R ³ is a member selected from the group consisting of H and halogen;
W is

A member selected from the group consisting of
Wherein Z ¹ , Z ² , and Z ³ are each independently N, C, or CH, and ^{two of} Z ¹ , Z ² , and Z ³ are other than N;
Z ⁴ is N;
Subscript n is an integer from 0 to 3 and subscript m is an integer from 0 to 1;
R ⁴ is halogen, —OR ^4a , —OC (O) R ^4a , —NR ^4a R ^4b , —SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R ^4b , —R ^4c , —CN, —NO ₂ , —CO ₂ R ^4a , —CONR ^4a R ^4b , —C (O) R ^4a , —OC (O) NR ^4a R ^4b , —NR ^4b C (O _{^{) R 4a, -NR 4b C (}} O) 2 R 4c, -NR 4a -C (O) NR 4a R 4b, -X 1 OR 4a, -X 1 OC (O) R 4a, -X 1 NR 4a R ^{4b, -X 1 SR 4a, -X} 1 S (O) R 4a, -X 1 S (O) 2 R 4a, -X 1 CN, -X 1 NO 2, -X 1 CO 2 R 4a, -O -X ¹ CO ₂ R ^4a , -X ¹ CONR ^4a R ^4b , -O-X ¹ CONR ^4a R ^4b -X ¹ C (O) R ^4a , -O-X ¹ NR ^4a R ^4b , -S (O) X ¹ NR ^4a R ^4b , -S (O) ₂ X ¹ NR ^4a R ^4b , -X ¹ OC (O) NR ^4a R ^4b , -X ¹ NR ^4a C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a C (O) NR ^4a R ^4b , -Y, A member selected from the group consisting of —X ¹ —Y, —O—Y, —NR ^4a Y, —SY, —S (O) Y and —S (O) ₂ Y;
R ^{4 ′} is —C (═NH) R ^4a , —C (═NR ^4c ) R ^4a , —C (═NH) NR ^4a R ^4b , —C (= NR ^4c ) NR ^4a R ^4b , —C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b , -X ² -C (= NH) NR ^4a R ^4b , -X ² -C (= NR ^4c ) NR ^4a R ^4b , -X ² -C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b and -C (= NR ^4a ) NR ^4a -Y is a member selected from the group consisting of:
Where Y is halogen, ^{oxo, -OR 4a, -OC (O)} R 4a, -NR 4a R 4b, -R 4c, -SR 4a, S (O) R 4a, S (O) 2 R 4a, S _{^{(O) 2 NR 4a R 4b}} , -CN, -NO 2, -CO 2 R 4a, -CONR 4a R 4b, -C (O) R 4a, -NR 4b C (O) R 4a, -NR 4b C _{^{(O) 2 R 4c, -X}} 1 R 4a, -X 1 OR 4a, -X 1 SR 4a, -X 1 S (O) R 4a, -X 1 S (O) 2 R 4a, -X 1 CN _{^{, -X 1 NO 2, -X 1}} CO 2 R 4a, -X 1 CONR 4a R 4b, -X 1 C (O) R 4a, -O-X 1 NR 4a R 4b, -S (O) X 1 _{^{NR 4a R 4b, -S (O}} ) 2 X 1 NR 4a R 4b, -X 1 OC (O) NR 4a R ^{b, -X 1 NR 4b C (} O) R 4a, -X 1 NR 4b C (O) 2 R 4c, -X 1 NR 4a -C (O) NR 4a R 4b, -X 1 OC (O) R ^{4a, -X 1 NR 4a R 4b} , -O-X 1 OR 4a, -O-X 1 NR 4a R 4b, -O-X 1 CO 2 R 4a, -O-X 1 CONR 4a R 4b, -NR ^{4b -X 1 oR 4a, -NR 4b} -X 1 NR 4a R 4b, -NR 4b -X 1 CO 2 R 4a, and ^-NR 4b ^-X 1 ^CONR 4a ^1~3 selected from the group consisting of ^{R 4b} 5- or 6-membered aryl, heterocyclyl or aryl-C _1-2 alkyl, optionally substituted by 1 substituent,
X ¹ and X ² are each a member independently selected from the group consisting of C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene;
R ^4a and R ^4b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl Independently selected from the group consisting of:, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
R ^4c is C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl, respectively. Independently selected from the group consisting of —C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
Optionally any two of R ^4a , R ^4b and R ^4c , when part of a common R ⁴ or R ^{4 ′} substituent, combine with 0 to 2 atoms each bonded to Can form a saturated or unsaturated, 4-9 membered monocyclic or bicyclic ring having as an additional heteroatom as a ring member;
R ^4a , R ^4b, and R ^4c are —OH, oxo, —R ^m , —OR ^m , —OC (O) NHR ^m , —OC (O) N (R ^m ) ₂ , —SH, —SR ^{m, respectively. _{-S (O) R m, -S}} (O) 2 R m, -SO 2 NH 2, -S (O) 2 NHR m, -S (O) 2 N (R m) 2, -NHS (O) _{^{2 R m, -NR m S (}} O) 2 R m, -C (O) NH 2, -C (O) NHR m, -C (O) N (R m) 2, -C (O) R m , —NHC (O) R ^m , —NR ^m C (O) R ^m , —NHC (O) NH ₂ , —NR ^m C (O) NH ₂ , —NR ^m C (O) NHR ^m , —NHC ( _{^{O) NHR m, -NR m C}} (O) N (R m) 2, -NHC (O) N (R m) 2, -CO 2 H, -CO 2 R m, -NHCO 2 R m, -NR _{^{m CO 2 R m, -CN,}} -NO 2, -NH 2, from _{^{-NHR m, -N (R m)}} 2, -NR m S (O) NH 2 and _{^{-NR m S (O) 2 NHR}} m May be further substituted with 1 to 3 members selected from the group consisting of wherein R ^m is each independently unsubstituted C _1-6 alkyl, benzyl, or an atom to which each is attached. In combination to form a saturated 4, 5, 6 or 7 membered ring having 0 to 2 additional heteroatoms as ring members;
R ⁵ represents —R ^5a , —CO ₂ R ^5c , —CONR ^5a R ^5b , —C (O) R ^5a , —C (═NH) NR ^5a R ^5b , —C (═NR ^5c ) NR ^5a R ^5b , ^{-C (= N + R 5c R} 5c) NR 5a R 5b, -C (= NR 5a) R 5a, -C (= NR 5a) Y 1, -X 3 OR 5a, -X 3 OC (O) R ^{5a, -X 3 NR 5a R 5b} , -X 3 SR 5a, -X 3 CN, -X 3 NO 2, -X 3 CO 2 R 5a, -X 3 CONR 5a R 5b, -X 3 C (O) ^{R 5a, -X 3 OC (O} ) NR 5a R 5b, -X 3 NR 5a C (O) R 5a, -X 3 NR 5b C (O) 2 R 5c, -X 3 NR 5a C (O) NR ^{5a R 5b, -X 3 -C (} = NR 5a) NR 5a R 5b, -Y 1, and Is a member selected from the group consisting of X ³ -Y ^1,
Wherein Y ¹ is ^{halogen, -OR 5a, -OC (O)} R 5a, -NR 5a R 5b, -R 5c, -SR 5a, -CN, -NO 2, -CO 2 R 5a, -CONR 5a R ^{5b, -C (O) R 5a} , -NR 5b C (O) R 5a, -NR 5b C (O) 2 R 5C, -X 3 OR 5a, -X 3 SR 5a, -X 3 CN, -X _{^{3 NO 2, -X 3 CO 2}} R 5a, -X 3 CONR 5a R 5b, -X 3 C (O) R 5a, -X 3 OC (O) NR 5a R 5b, -X 3 NR 5b C (O _{^{) R 5a, -X 3 NR 5b}} C (O) 2 R 5c, -X 3 NR 5a -C (O) NR 5a R 5b, -X 3 OC (O) R 5a, -X 3 NR 5a R 5b, ^{-O-X 3 OR 5a, -O} -X 3 NR 5a R 5b, -O-X 3 CO ^{R 5a, -O-X 3 CONR} 5a R 5b, -NR 5b -X 3 OR 5a, -NR 5b -X 3 NR 5a R 5b, -NR 5b -X 3 CO 2 R 5a, and ^-NR 5b -X ³ CONR ^5a R ^5b is a 5- or 6-membered aryl or heteroaryl ring or aryl-C _1-2 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of:
Each X ³ is a member independently selected from the group consisting of C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene;
R ^5a and R ^5b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl Independently selected from the group consisting of:, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
R ^5c is C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl, respectively. Independently selected from the group consisting of —C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
Optionally, any two of R ^5a , R ^5b and R ^5c , when part of a common R ⁵ substituent, combine with the atom to which each is attached to form 0 to 1 additional hetero Can form saturated 4, 5, 6 or 7 membered rings having atoms as ring members;
R ^5a , R ^5b and R ^5c are —OH, —OR ⁿ , —OC (O) NHR ⁿ , —OC (O) N (R ⁿ ) ₂ , —SH, —SR ⁿ —S (O) R, respectively. _{^{n, -S (O) 2 R}} n, -SO 2 NH 2, -S (O) 2 NHR n, -S (O) 2 n (R n) 2, -NHS (O) 2 R n, -NR _{^{n S (O) 2 R n}} , -C (O) NH 2, -C (O) NHR n, -C (O) n (R n) 2, -C (O) R n, -NHC (O) _{^{R n, -NR n C (O}} ) R n, -NHC (O) NH 2, -NR n C (O) NH 2, -NR n C (O) NHR n, -NHC (O) NHR n, - _{^{NR n C (O) n (}} R n) 2, -NHC (O) n (R n) 2, -CO 2 H, -CO 2 R n, -NHCO 2 R n, -NR n CO 2 R n _-CN, is selected from the group consisting of _{^{-NO 2, -NH 2, -NHR n}} , -N (R n) 2, -NR n S (O) NH 2 and _{^{-NR n S (O) 2 NHR}} n It may be further substituted with 1 to 3 members, wherein each R ⁿ is independently unsubstituted C _1-6 alkyl or benzyl. W has formula (a), a compound of any one of claims 1 to 3 and 5 to 13. Having the formula, according to claim 1 Symbol placement compounds:

Or a pharmaceutically acceptable salt thereof, wherein A is halogen, R ^A , —OR ^A , N (R ^A ) ₂ , CO ₂ R ^A , CON (R ^A ) ₂ , S (O) _{0 selected from 2} R ^A , S (O) ₂ N (R ^A ) ₂ , X ¹ OR ^A , X ¹ CO ₂ R ^A , X ¹ CON (R ^A ) ₂ , X ¹ N (R ^A ) ₂ Isoxazole, isothiazole, pyrazole, imidazole, oxazole, thiazole, isoxazoline, pyrazoline, imidazoline, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-, having -4 substituents Represents a group selected from the group consisting of oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, pyrrolidine, pyrrole, furan and thiophene. Wherein each R ^A is independently selected from H, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, or optionally two R ^A bonded to the same atom Combine to form a 3-, 4-, 5-, 6- or 7-membered ring;
R is a member selected from the group consisting of H and C _1-4 alkyl ;
R ¹ is a member selected from the group consisting of halogen, C _1-8 alkyl, C _2-8 alkenyl and C _2-8 alkynyl;
R ² is selected from the group consisting of H, C _1-8 alkyl, —X—OR ^2a , —X—SR ^2a , —X—COR ^2a , —X—CO ₂ R ^2a and —XN (R ^2a ) _2. Wherein X is C _1-8 alkylene, and each R ^2a is independently selected from the group consisting of H and C _1-8 alkyl, or optionally on the same nitrogen atom. Two attached R ^2a groups combine to form a 4-, 5-, 6- or 7-membered ring;
R ³ is a member selected from the group consisting of H and C _1-4 alkyl; or if R ³ is present, be present if there is a carbon-carbon double bond in the ring to which it is attached. Z;
W is

A member selected from the group consisting of
Wherein Z ¹ , Z ² , and Z ³ are each independently N, C, or CH, and ^{two of} Z ¹ , Z ² , and Z ³ are other than N;
Subscript n is an integer from 0 to 3 and subscript m is an integer from 0 to 1;
R ⁴ is halogen, —OR ^4a , —OC (O) R ^4a , —NR ^4a R ^4b , —SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R _{^{4b, -R 4c, -CN, -NO}} 2, -CO 2 R 4a, -CONR 4a R 4b, -C (O) R 4a, -OC (O) NR 4a R 4b, -NR 4b C (O) _{^{R 4a, -NR 4b C (O}} ) 2 R 4c, -NR 4a -C (O) NR 4a R 4b, -X 1 OR 4a, -X 1 OC (O) R 4a, -X 1 NR 4a R 4b ^{, -X 1 SR 4a, -X 1} S (O) R 4a, -X 1 S (O) 2 R 4a, -X 1 CN, -X 1 NO 2, -X 1 CO 2 R 4a, -O- _{^{X 1 CO 2 R 4a, -X}} 1 CONR 4a R 4b, -O-X 1 CONR 4a R 4b, ^{-X 1 C (O) R 4a} , -O-X 1 NR 4a R 4b, -S (O) X 1 NR 4a R 4b, -S (O) 2 X 1 NR 4a R 4b, -X 1 OC ( O) NR ^4a R ^4b , -X ¹ NR ^4a C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a C (O) NR ^4a R ^4b , -Y,- A member selected from the group consisting of X ¹ -Y, —O—Y, —NR ^4a Y, —SY, —S (O) Y and —S (O) ₂ Y;
R ^{4 ′} is —C (═NH) R ^4a , —C (═NR ^4c ) R ^4a , —C (═NH) NR ^4a R ^4b , —C (= NR ^4c ) NR ^4a R ^4b , —C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b , -X ² -C (= NH) NR ^4a R ^4b , -X ² -C (= NR ^4c ) NR ^4a R ^4b , -X ² -C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b and -C (= NR ^4a ) NR ^4a -Y is a member selected from the group consisting of:
Where Y is halogen, ^{oxo, -OR 4a, -OC (O)} R 4a, -NR 4a R 4b, -R 4c, -SR 4a, S (O) R 4a, S (O) 2 R 4a, S _{^{(O) 2 NR 4a R 4b}} , -CN, -NO 2, -CO 2 R 4a, -CONR 4a R 4b, -C (O) R 4a, -NR 4b C (O) R 4a, -NR 4b C _{^{(O) 2 R 4c, -X}} 1 R 4a, -X 1 OR 4a, -X 1 SR 4a, -X 1 S (O) R 4a, -X 1 S (O) 2 R 4a, -X 1 CN _{^{, -X 1 NO 2, -X 1}} CO 2 R 4a, -X 1 CONR 4a R 4b, -X 1 C (O) R 4a, -O-X 1 NR 4a R 4b, -S (O) X 1 _{^{NR 4a R 4b, -S (O}} ) 2 X 1 NR 4a R 4b, -X 1 OC (O) NR 4a R ^{b, -X 1 NR 4b C (} O) R 4a, -X 1 NR 4b C (O) 2 R 4c, -X 1 NR 4a -C (O) NR 4a R 4b, -X 1 OC (O) R ^{4a, -X 1 NR 4a R 4b} , -O-X 1 OR 4a, -O-X 1 NR 4a R 4b, -O-X 1 CO 2 R 4a, -O-X 1 CONR 4a R 4b, -NR ^{4b -X 1 oR 4a, -NR 4b} -X 1 NR 4a R 4b, -NR 4b -X 1 CO 2 R 4a, and ^-NR 4b ^-X 1 ^CONR 4a ^1~3 selected from the group consisting of ^{R 4b} 5- or 6-membered aryl, heterocyclyl or aryl-C _1-2 alkyl, optionally substituted by 1 substituent,
X ¹ and X ² are each a member independently selected from the group consisting of C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene;
R ^4a and R ^4b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl Independently selected from the group consisting of:, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
R ^4c is C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl, respectively. Independently selected from the group consisting of —C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
Optionally any two of R ^4a , R ^4b and R ^4c , when part of a common R ⁴ or R ^{4 ′} substituent, combine with 0 to 2 atoms each bonded to Can form a saturated or unsaturated, 4-9 membered monocyclic or bicyclic ring having as an additional heteroatom as a ring member;
R ^4a , R ^4b, and R ^4c are —OH, oxo, —R ^m , —OR ^m , —OC (O) NHR ^m , —OC (O) N (R ^m ) ₂ , —SH, —SR ^{m, respectively. _{-S (O) R m, -S}} (O) 2 R m, -SO 2 NH 2, -S (O) 2 NHR m, -S (O) 2 N (R m) 2, -NHS (O) _{^{2 R m, -NR m S (}} O) 2 R m, -C (O) NH 2, -C (O) NHR m, -C (O) N (R m) 2, -C (O) R m , —NHC (O) R ^m , —NR ^m C (O) R ^m , —NHC (O) NH ₂ , —NR ^m C (O) NH ₂ , —NR ^m C (O) NHR ^m , —NHC ( _{^{O) NHR m, -NR m C}} (O) N (R m) 2, -NHC (O) N (R m) 2, -CO 2 H, -CO 2 R m, -NHCO 2 R m, -NR _{^{m CO 2 R m, -CN,}} -NO 2, -NH 2, from _{^{-NHR m, -N (R m)}} 2, -NR m S (O) NH 2 and _{^{-NR m S (O) 2 NHR}} m May be further substituted with 1 to 3 members selected from the group consisting of wherein R ^m is each independently unsubstituted C _1-6 alkyl, benzyl, or an atom to which each is attached. In combination to form a saturated 4, 5, 6 or 7 membered ring having 0 to 2 additional heteroatoms as ring members;
R ⁵ represents —R ^5a , —CO ₂ R ^5c , —CONR ^5a R ^5b , —C (O) R ^5a , —C (═NH) NR ^5a R ^5b , —C (═NR ^5c ) NR ^5a R ^5b , ^{-C (= N + R 5c R} 5c) NR 5a R 5b, -C (= NR 5a) R 5a, -C (= NR 5a) Y 1, -X 3 OR 5a, -X 3 OC (O) R ^{5a, -X 3 NR 5a R 5b} , -X 3 SR 5a, -X 3 CN, -X 3 NO 2, -X 3 CO 2 R 5a, -X 3 CONR 5a R 5b, -X 3 C (O) ^{R 5a, -X 3 OC (O} ) NR 5a R 5b, -X 3 NR 5a C (O) R 5a, -X 3 NR 5b C (O) 2 R 5c, -X 3 NR 5a C (O) NR ^{5a R 5b, -X 3 -C (} = NR 5a) NR 5a R 5b, -Y 1, and Is a member selected from the group consisting of X ³ -Y ^1,
Wherein Y ¹ is ^{halogen, -OR 5a, -OC (O)} R 5a, -NR 5a R 5b, -R 5c, -SR 5a, -CN, -NO 2, -CO 2 R 5a, -CONR 5a R ^{5b, -C (O) R 5a} , -NR 5b C (O) R 5a, -NR 5b C (O) 2 R 5C, -X 3 OR 5a, -X 3 SR 5a, -X 3 CN, -X _{^{3 NO 2, -X 3 CO 2}} R 5a, -X 3 CONR 5a R 5b, -X 3 C (O) R 5a, -X 3 OC (O) NR 5a R 5b, -X 3 NR 5b C (O _{^{) R 5a, -X 3 NR 5b}} C (O) 2 R 5c, -X 3 NR 5a -C (O) NR 5a R 5b, -X 3 OC (O) R 5a, -X 3 NR 5a R 5b, ^{-O-X 3 OR 5a, -O} -X 3 NR 5a R 5b, -O-X 3 CO ^{R 5a, -O-X 3 CONR} 5a R 5b, -NR 5b -X 3 OR 5a, -NR 5b -X 3 NR 5a R 5b, -NR 5b -X 3 CO 2 R 5a, and ^-NR 5b -X ³ CONR ^5a R ^5b is a 5- or 6-membered aryl or heteroaryl ring or aryl-C _1-2 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of:
Each X ³ is a member independently selected from the group consisting of C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene;
R ^5a and R ^5b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl Independently selected from the group consisting of:, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
R ^5c is C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl, respectively. Independently selected from the group consisting of —C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
Optionally, any two of R ^5a , R ^5b and R ^5c , when part of a common R ⁵ substituent, combine with the atom to which each is attached to form 0 to 1 additional hetero Can form saturated 4, 5, 6 or 7 membered rings having atoms as ring members;
R ^5a , R ^5b and R ^5c are —OH, —OR ⁿ , —OC (O) NHR ⁿ , —OC (O) N (R ⁿ ) ₂ , —SH, —SR ⁿ —S (O) R, respectively. _{^{n, -S (O) 2 R}} n, -SO 2 NH 2, -S (O) 2 NHR n, -S (O) 2 n (R n) 2, -NHS (O) 2 R n, -NR _{^{n S (O) 2 R n}} , -C (O) NH 2, -C (O) NHR n, -C (O) n (R n) 2, -C (O) R n, -NHC (O) _{^{R n, -NR n C (O}} ) R n, -NHC (O) NH 2, -NR n C (O) NH 2, -NR n C (O) NHR n, -NHC (O) NHR n, - _{^{NR n C (O) n (}} R n) 2, -NHC (O) n (R n) 2, -CO 2 H, -CO 2 R n, -NHCO 2 R n, -NR n CO 2 R n _-CN, is selected from the group consisting of _{^{-NO 2, -NH 2, -NHR n}} , -N (R n) 2, -NR n S (O) NH 2 and _{^{-NR n S (O) 2 NHR}} n It may be further substituted with 1 to 3 members, wherein each R ⁿ is independently unsubstituted C _1-6 alkyl or benzyl. A is isoxazole, isothiazole, pyrazole, imidazole, oxazole, thiazole, isoxazoline, pyrazoline, imidazoline, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3 , 4-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, pin Roridin, pyrrole, is a member selected from the group consisting of furan and thiophene, according to claim 1 to 10 and 15 A compound according to any one of the above. A is

R ³ is selected from the group consisting of: halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, OR ^3a , N (R ^3a ) ₂ , X ⁰ CO ₂ R ^3a , X ⁰ CON (R ^3a ) ₂ , SO ₂ C _1-4 alkyl , SO ₂ N (R ^3a ) ₂ is independently selected; R ^3a is H, C _1-8 alkyl, C _2-8 , respectively. Independently selected from the group consisting of alkenyl and C _2-8 alkynyl; and X ⁰ is a bond or C _1-8 alkylene; and the dashed line indicates the point of attachment to A and the wavy line indicates the bond to the rest of the molecule 16. A compound according to any one of claims 1 to 10 and 15 , which exhibits a point. 18. A compound according to any one of claims 15 to 17 , wherein W has the formula (a). 18. A compound according to any one of claims 15 to 17 , wherein W has the formula (b). 18. A compound according to any one of claims 15 to 17 , wherein W has the formula (c). Having the formula, according to claim 1, wherein the compound:

Or a pharmaceutically acceptable salt thereof, wherein R is a member selected from the group consisting of H and C _1-4 alkyl ;
R ¹ is a member selected from the group consisting of halogen, C _1-8 alkyl, C _2-8 alkenyl and C _2-8 alkynyl;
R ² is selected from the group consisting of H, C _1-8 alkyl, —X—OR ^2a , —X—SR ^2a , —X—COR ^2a , —X—CO ₂ R ^2a and —XN (R ^2a ) _2. Wherein X is C _1-8 alkylene, and each R ^2a is independently selected from the group consisting of H and C _1-8 alkyl, or optionally on the same nitrogen atom. Two attached R ^2a groups combine to form a 4-, 5-, 6- or 7-membered ring;
Each dashed line independently represents an arbitrary bond, where there is only one optional bond;
R ³ is a member selected from the group consisting of H and C _1-4 alkyl; or if R ³ is present, be present if there is a carbon-carbon double bond in the ring to which it is attached. Z;
W is

A member selected from the group consisting of
Wherein Z ¹ , Z ² , and Z ³ are each independently N, C, or CH, and ^{two of} Z ¹ , Z ² , and Z ³ are other than N;
Subscript n is an integer from 0 to 3 and subscript m is an integer from 0 to 1;
R ⁴ is halogen, —OR ^4a , —OC (O) R ^4a , —NR ^4a R ^4b , —SR ^4a , S (O) R ^4a , S (O) ₂ R ^4a , S (O) ₂ NR ^4a R _{^{4b, -R 4c, -CN, -NO}} 2, -CO 2 R 4a, -CONR 4a R 4b, -C (O) R 4a, -OC (O) NR 4a R 4b, -NR 4b C (O) _{^{R 4a, -NR 4b C (O}} ) 2 R 4c, -NR 4a -C (O) NR 4a R 4b, -X 1 OR 4a, -X 1 OC (O) R 4a, -X 1 NR 4a R 4b ^{, -X 1 SR 4a, -X 1} S (O) R 4a, -X 1 S (O) 2 R 4a, -X 1 CN, -X 1 NO 2, -X 1 CO 2 R 4a, -O- _{^{X 1 CO 2 R 4a, -X}} 1 CONR 4a R 4b, -O-X 1 CONR 4a R 4b, ^{-X 1 C (O) R 4a} , -O-X 1 NR 4a R 4b, -S (O) X 1 NR 4a R 4b, -S (O) 2 X 1 NR 4a R 4b, -X 1 OC ( O) NR ^4a R ^4b , -X ¹ NR ^4a C (O) R ^4a , -X ¹ NR ^4b C (O) ₂ R ^4c , -X ¹ NR ^4a C (O) NR ^4a R ^4b , -Y,- A member selected from the group consisting of X ¹ -Y, —O—Y, —NR ^4a Y, —SY, —S (O) Y and —S (O) ₂ Y;
R ^{4 ′} is —C (═NH) R ^4a , —C (═NR ^4c ) R ^4a , —C (═NH) NR ^4a R ^4b , —C (= NR ^4c ) NR ^4a R ^4b , —C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b , -X ² -C (= NH) NR ^4a R ^4b , -X ² -C (= NR ^4c ) NR ^4a R ^4b , -X ² -C (= N ⁺ R ^4c R ^4c ) NR ^4a R ^4b and -C (= NR ^4a ) NR ^4a -Y is a member selected from the group consisting of:
Where Y is halogen, ^{oxo, -OR 4a, -OC (O)} R 4a, -NR 4a R 4b, -R 4c, -SR 4a, S (O) R 4a, S (O) 2 R 4a, S _{^{(O) 2 NR 4a R 4b}} , -CN, -NO 2, -CO 2 R 4a, -CONR 4a R 4b, -C (O) R 4a, -NR 4b C (O) R 4a, -NR 4b C _{^{(O) 2 R 4c, -X}} 1 R 4a, -X 1 OR 4a, -X 1 SR 4a, -X 1 S (O) R 4a, -X 1 S (O) 2 R 4a, -X 1 CN _{^{, -X 1 NO 2, -X 1}} CO 2 R 4a, -X 1 CONR 4a R 4b, -X 1 C (O) R 4a, -O-X 1 NR 4a R 4b, -S (O) X 1 _{^{NR 4a R 4b, -S (O}} ) 2 X 1 NR 4a R 4b, -X 1 OC (O) NR 4a R ^{b, -X 1 NR 4b C (} O) R 4a, -X 1 NR 4b C (O) 2 R 4c, -X 1 NR 4a -C (O) NR 4a R 4b, -X 1 OC (O) R ^{4a, -X 1 NR 4a R 4b} , -O-X 1 OR 4a, -O-X 1 NR 4a R 4b, -O-X 1 CO 2 R 4a, -O-X 1 CONR 4a R 4b, -NR ^{4b -X 1 oR 4a, -NR 4b} -X 1 NR 4a R 4b, -NR 4b -X 1 CO 2 R 4a, and ^-NR 4b ^-X 1 ^CONR 4a ^1~3 selected from the group consisting of ^{R 4b} 5 or 6-membered aryl, heterocyclyl or aryl-C _1-2 alkyl, optionally substituted by 1 substituent, wherein X ¹ and X ² are C _1-4 alkylene, C _2-4 alkenylene and C, respectively. _2-4 Al It is a member selected independently from the group consisting of vinylene;
R ^4a and R ^4b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl Independently selected from the group consisting of:, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
R ^4c is C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl, respectively. Independently selected from the group consisting of —C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
Optionally any two of R ^4a , R ^4b and R ^4c , when part of a common R ⁴ or R ^{4 ′} substituent, combine with 0 to 2 atoms each bonded to Can form a saturated or unsaturated, 4-9 membered monocyclic or bicyclic ring having as an additional heteroatom as a ring member;
R ^4a , R ^4b, and R ^4c are —OH, oxo, —R ^m , —OR ^m , —OC (O) NHR ^m , —OC (O) N (R ^m ) ₂ , —SH, —SR ^{m, respectively. _{-S (O) R m, -S}} (O) 2 R m, -SO 2 NH 2, -S (O) 2 NHR m, -S (O) 2 N (R m) 2, -NHS (O) _{^{2 R m, -NR m S (}} O) 2 R m, -C (O) NH 2, -C (O) NHR m, -C (O) N (R m) 2, -C (O) R m , —NHC (O) R ^m , —NR ^m C (O) R ^m , —NHC (O) NH ₂ , —NR ^m C (O) NH ₂ , —NR ^m C (O) NHR ^m , —NHC ( _{^{O) NHR m, -NR m C}} (O) N (R m) 2, -NHC (O) N (R m) 2, -CO 2 H, -CO 2 R m, -NHCO 2 R m, -NR _{^{m CO 2 R m, -CN,}} -NO 2, -NH 2, from _{^{-NHR m, -N (R m)}} 2, -NR m S (O) NH 2 and _{^{-NR m S (O) 2 NHR}} m May be further substituted with 1 to 3 members selected from the group consisting of wherein R ^m is each independently unsubstituted C _1-6 alkyl, benzyl, or an atom to which each is attached. In combination to form a saturated 4, 5, 6 or 7 membered ring having 0 to 2 additional heteroatoms as ring members;
R ⁵ is —R ^5a , —CO ₂ R ^5c , —CONR ^5a R ^5b , —C (O) R ^5a , C (= NR ^5a ) NR ^5a R ^5b , —C (= N ⁺ R ^5c R ^5c ) NR ^{5a R 5b, -C (= NR} 5a) R 5a, -C (= NR 5a) Y 1, -X 3 OR 5a, -X 3 OC (O) R 5a, -X 3 NR 5a R 5b, -X ³ SR ^5a , -X ³ CN, -X ³ NO ₂ , -X ³ CO ₂ R ^5a , -X ³ CONR ^5a R ^5b , -X ³ C (O) R ^5a , -X ³ OC (O) NR ^{5a R 5b, -X 3 NR 5a C} (O) R 5a, -X 3 NR 5b C (O) 2 R 5c, -X 3 NR 5a C (O) NR 5a R 5b, -X 3 -C (= NR ^5a ) selected from the group consisting of NR ^5a R ^5b , -Y ¹ , and -X ³ -Y ¹ A member who
Wherein Y ¹ is ^{halogen, -OR 5a, -OC (O)} R 5a, -NR 5a R 5b, -R 5c, -SR 5a, -CN, -NO 2, -CO 2 R 5a, -CONR 5a R ^{5b, -C (O) R 5a} , -NR 5b C (O) R 5a, -NR 5b C (O) 2 R 5C, -X 3 OR 5a, -X 3 SR 5a, -X 3 CN, -X _{^{3 NO 2, -X 3 CO 2}} R 5a, -X 3 CONR 5a R 5b, -X 3 C (O) R 5a, -X 3 OC (O) NR 5a R 5b, -X 3 NR 5b C (O _{^{) R 5a, -X 3 NR 5b}} C (O) 2 R 5c, -X 3 NR 5a -C (O) NR 5a R 5b, -X 3 OC (O) R 5a, -X 3 NR 5a R 5b, ^{-O-X 3 OR 5a, -O} -X 3 NR 5a R 5b, -O-X 3 CO ^{R 5a, -O-X 3 CONR} 5a R 5b, -NR 5b -X 3 OR 5a, -NR 5b -X 3 NR 5a R 5b, -NR 5b -X 3 CO 2 R 5a, and ^-NR 5b -X ³ CONR ^5a R ^5b is a 5- or 6-membered aryl or heteroaryl ring or aryl-C _1-2 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of:
Each X ³ is a member independently selected from the group consisting of C _1-4 alkylene, C _2-4 alkenylene and C _2-4 alkynylene;
R ^5a and R ^5b are each hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl Independently selected from the group consisting of:, heteroaryl, aryl-C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
R ^5c is C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, heteroaryl, aryl, respectively. Independently selected from the group consisting of —C _1-4 alkyl, and aryloxy-C _1-4 alkyl;
Optionally, any two of R ^5a , R ^5b and R ^5c , when part of a common R ⁵ substituent, combine with the atom to which each is attached to form 0 to 1 additional hetero Can form saturated 4, 5, 6 or 7 membered rings having atoms as ring members;
R ^5a , R ^5b and R ^5c are —OH, —OR ⁿ , —OC (O) NHR ⁿ , —OC (O) N (R ⁿ ) ₂ , —SH, —SR ⁿ —S (O) R, respectively. _{^{n, -S (O) 2 R}} n, -SO 2 NH 2, -S (O) 2 NHR n, -S (O) 2 n (R n) 2, -NHS (O) 2 R n, -NR _{^{n S (O) 2 R n}} , -C (O) NH 2, -C (O) NHR n, -C (O) n (R n) 2, -C (O) R n, -NHC (O) _{^{R n, -NR n C (O}} ) R n, -NHC (O) NH 2, -NR n C (O) NH 2, -NR n C (O) NHR n, -NHC (O) NHR n, - _{^{NR n C (O) n (}} R n) 2, -NHC (O) n (R n) 2, -CO 2 H, -CO 2 R n, -NHCO 2 R n, -NR n CO 2 R n _-CN, is selected from the group consisting of _{^{-NO 2, -NH 2, -NHR n}} , -N (R n) 2, -NR n S (O) NH 2 and _{^{-NR n S (O) 2 NHR}} n It may be further substituted with 1 to 3 members, wherein each R ⁿ is independently unsubstituted C _1-6 alkyl or benzyl. 24. The compound of claim 21 , wherein W has the formula (a). 24. The compound of claim 21 , wherein W has the formula (b). 24. The compound of claim 21 , wherein W has the formula (c).   Compound selected from the group consisting of: 5-chloro-thiophene-2-carboxylic acid [3- (4-bromo-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro- Thiophene-2-carboxylic acid [3- (3-bromo-phenyl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-phenoxy-phenyl) -4,5 -Dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N-methylcarbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-Chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-i Methyl} -methyl-amide; methyl 5-chloro-thiophene-2-carboxylate- {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazole- 5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide; 5 -Chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide; 1-{[4- (5- {[(5-Chloro-thiophene-2-carbonyl) -methyl-amino] -methyl} -isoxazol-3-yl) -phenyl] -imino-methyl} -piperidine- -Carboxylic acid ethyl ester; 5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-imino-methyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide; Chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-azetidin-1-ylidene-methyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide; 5-chloro-thiophene- 2-carboxylic acid {3- [4- (N-ethyl-N-methyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -methyl-amide; methyl 5-chloro-thiophene-2-carboxylate -{3- [4- (N-methyl-N-propyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide 5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-dimethylamino-ethyl) -N-methyl-carbamimidoyl] -phenyl} -isoxazol-5-ylmethyl) -methyl 1-{[4- (5-{[(5-chloro-thiophen-2-carbonyl) -methyl-amino] -methyl} -isoxazol-3-yl) -phenyl] -imino-methyl} -piperidine -4-carboxylic acid amide; 5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-methoxy-ethyl) -N-methyl-carbamimidoyl] -phenyl} -isoxazole-5 -Ylmethyl) -methyl-amide; methyl 5-chloro-thiophene-2-carboxylate- {3- [4- (N-methyl-N-prop-2-ynyl-carbamimidoyl) -phen L) -Isoxazol-5-ylmethyl} -amide; (R) -5-chloro-thiophene-2-carboxylic acid (1- {3- [4- (imino-piperidin-1-yl-methyl) -phenyl]- Isoxazol-5-yl} -ethyl) -amide; (R) -5-chloro-thiophene-2-carboxylic acid (1- {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -Isoxazol-5-yl} -ethyl) -amide; (S) -5-chloro-thiophene-2-carboxylic acid (1- {3- [4- (1-methyl-4,5-dihydro-1H-imidazole) -2-yl) -phenyl] -isoxazol-5-yl} -ethyl) -amide; (S) -5-chloro-thiophene-2-carboxylic acid (1- {3- [4- (imino-pyrrolidine-1 -Yl-methyl) -pheny ] -Isoxazol-5-yl} -ethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-pyrrolidin-1-yl- Phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-methylsulfanyl -Phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid (3-phenyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2 Carboxylic acid (5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2 Carboxylic acid (3-phenyl-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid (3-p-tolyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide; 5 -Chloro-thiophene-2-carboxylic acid (5-methyl-3-p-tolyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid (3-p- Tolyl-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-methoxy-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro -Thiophen-2-carboxylic acid [3- (4-methoxy-phenyl) -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl] Amido; 5-chloro-thiophene-2-carboxylic acid [3- (4-methoxy-phenyl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-chloro- Phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-chloro-phenyl) -5-methyl-4,5-dihydro-isoxazole -5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-chloro-phenyl) -isoxazol-5-ylmethyl] -amide; 4- (5-{[(5-chloro- Thiophene-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -benzoic acid methyl ester; 4- (5-{[(5- Loro-thiophen-2-carbonyl) -amino] -methyl} -isoxazol-3-yl) -benzoic acid methyl ester; 4- (5-{[(5-chloro-thiophen-2-carbonyl) -amino] -methyl } -4,5-dihydro-isoxazol-3-yl) -benzoic acid; 4- (5-{[(5-chloro-thiophen-2-carbonyl) -amino] -methyl} -isoxazol-3-yl)- Benzoic acid; 5-chloro-thiophene-2-carboxylic acid [3- (4-amino-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid ( 3- {4-[(2-diethylamino-ethyl) -methyl-carbamoyl] -phenyl} -isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2 -Carboxylic acid [3- (1-ethyl-piperidin-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (1-benzyl -Piperidin-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (1-isopropyl-piperidin-4-yl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (1-carbamimidoyl-piperidin-4-yl) -4,5-dihydro-isoxazole-5 -Ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid {3- [1- (1-imino-ethyl) -piperidin-4-yl] -4,5-dihydride -Isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [1- (imino-phenyl-methyl) -piperidin-4-yl] -4,5-dihydro-isoxazol-5 -Ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [1- (imino-pyridin-2-yl-methyl) -piperidin-4-yl] -4,5-dihydro-isoxazole-5 -Ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid (3-piperidin-4-yl-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid [3- (1- Ethyl-piperidin-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (1-benzyl- Peridin-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (1-carbamimidoyl-piperidin-4-yl) -isoxazol-5-ylmethyl] -Amide; 5-chloro-thiophene-2-carboxylic acid {3- [1- (1-imino-ethyl) -piperidin-4-yl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophen-2 -Carboxylic acid {3- [1- (imino-phenyl-methyl) -piperidin-4-yl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2'- Formyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2′-chloro-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2′-methylsulfanyl-biphenyl-) 4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-pyridin-4-yl-phenyl) -4,5-dihydro -Isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-pyridin-3-yl-phenyl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene- 2-Carboxylic acid [3- (2′-Azepan-1-ylmethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl]- 5-chloro-thiophene-2-carboxylic acid [3- (2′-dimethylaminomethyl-5′-methoxy-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2′-hydroxymethyl-4′-methoxy-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; -Thiophene-2-carboxylic acid [3- (3'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- ( 4'-dimethylaminomethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic [3- (4′-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2′-dimethylaminomethyl- 5′-methoxy-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-pyridin-2-yl-phenyl) -isoxazol-5 Ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-benzylamino-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophen-2- Carboxylic acid [3- (4-phenylamino-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro- Thiophene-2-carboxylic acid {3- [4- (4-fluoro-phenylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid { 3- [4- (Pyridin-2-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (2- Methyl-pyridin-4-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid (3- {4-[(2-amino-pyrimidine -4-yl) -methyl-amino] -phenyl} -4,5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carbo Acid {3- [4- (2-Ethyl-2H-pyrazol-3-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid [ 3- (4-morpholin-4-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (2-methoxymethyl) -Pyrrolidin-1-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (5-oxo) -[1,4] oxazepan-4-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid [ -(4-Phenylamino-phenyl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (4-methoxy-phenylamino) -phenyl] -isoxazole-5 -Ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-2-ylamino) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophen-2- Carboxylic acid {3- [4- (methyl-pyridin-4-yl-amino) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-pyrrolidine- 1-yl-phenyl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-morpho Phospho-4-yl-phenyl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-benzylamino-phenyl) -isoxazol-5-ylmethyl] -amide; 5 -Chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-piperidin-4-ylamino) -phenyl] -isoxazol-5-ylmethyl} -amide; 2- [4- (5-{[( 5-chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenylamino] -benzoic acid methyl ester; 3- [4- (5-{[( 5-chloro-thiophene-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenylamino] -benzoic acid methyl ester 4- [4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenylamino] -methyl benzoate Ester; 5-chloro-thiophene-2-carboxylic acid [3- (2′-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro -Thiophene-2-carboxylic acid [3- (3'-dimethylaminomethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (3′-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro Thiophene-2-carboxylic acid [3- (4′-dimethylaminomethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [ 3- (4′-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2 ′ -Dimethylaminomethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (3'-dimethylaminomethyl-biphenyl-3-yl) -isoxazole -5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (3'-pyrrolidin-1-ylmethyl-bif Enyl-3-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4′-dimethylaminomethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -Amide; 5-chloro-thiophene-2-carboxylic acid [3- (4'-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophen-2- Carboxylic acid [3- (3-pyridin-3-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (3-pyridine- 4-yl-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; and 5-chloro-thiophene-2-carboxylic acid 3- (3-pyridin-3-yl-phenyl) - - isoxazol-5-ylmethyl] - amide.   A compound selected from the group consisting of: 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -4,5-dihydro-isoxazole-5 -Ylmethyl} -amide; 1-{[4- (5-{[(5-chloro-thiophen-2-carbonyl) -amino] -methyl} -4,5-dihydro-isoxazol-3-yl) -phenyl] -Imino-methyl} -piperidine-4-carboxylic acid ethyl ester; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N-methyl-N-prop-2-ynyl-carbamimidoyl)- Phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-methoxy-ethyl) -N- Tyl-carbamimidoyl] -phenyl} -4,5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N-furan-2-ylmethyl) -N-methyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N-methyl- N-prop-2-ynyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-methoxy- Ethyl) -N-methyl-carbamimidoyl] -phenyl} -5-methyl-4,5-dihydro-isoxazol-5-ylmethyl) -amide; 1-{[4- (5-{[ 5-chloro-thiophen-2-carbonyl) -amino] -methyl} -5-methyl-4,5-dihydro-isoxazol-3-yl) -phenyl] -imino-methyl} -piperidine-4-carboxylic acid amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-fluoro-phenyl] -dihydro-isoxazol-5-ylmethyl} -amide; -Thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5 -Chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -fur Enyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (imino-pyrrolidin-1-yl-methyl) -Phenyl] -4,5-dihydro-isoxazol-5-ylmethyl-amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-pyrrolidine -1-yl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro- 1H-imidazol-2-yl) -2-pyrrolidin-1-yl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene 2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-pyrrolidin-1-yl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; Chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -2-morpholin-4-yl-phenyl] -4,5-dihydro -Isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-morpholin-4-yl-phenyl] -4 , 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-morpholine -4-yl-phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-[(2-methoxy-ethyl) -methyl- Amino] -4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophen-2 -Carboxylic acid (3- {4- (imino-pyrrolidin-1-yl-methyl) -2-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -4,5-dihydro-isoxazole-5 Ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid (3- {4- (imino-piperidin-1-yl-methyl) -2-[(2-methoxy-ethyl) -methyl-amino] -Phenyl} -4,5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-azepan-1-yl-4- (N, N-dimethyl-) Carbamimidoyl) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (2-methyl-pyrrolidine-1-carbonyl) ) -Phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (pyrrolidine-1-carbonyl) -phenyl] -isoxazole-5 -Ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2'-amino-biphenyl-4-yl) -4,5-dihydro-isoxa 5-chloro-thiophene-2-carboxylic acid [3- (2′-trifluoromethyl-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl]- Amido; 5-chloro-thiophene-2-carboxylic acid [3- (2′-methoxy-biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophen-2 -Carboxylic acid [3- (2'-methoxymethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-pyridin-3-yl -Phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (5'-chloro-2 ' {[(2-Methoxy-ethyl) -methyl-amino] -methyl} -biphenyl-4-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2′-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (3′-dimethylaminomethyl- Biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (2-chloro-pyridin-4-ylamino) -phenyl] -4,5 -Dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (pyrimidin-4-ylamino)- Phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-1H-pyrazol-3-ylamino) -phenyl] -4,5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (4-methyl-piperazin-1-yl) -phenyl] -4,5 -Dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-piperidin-4-ylamino) -phenyl] -4,5-dihydro-isoxazole -5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid (3- {4-[(2-dimethylamino-ethyl) -methyl-amino] -phen L} -4,5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (2-oxo-piperidin-1-yl) -phenyl] -4 , 5-dihydro-isoxazol-5-ylmethyl} -amide; and 5-chloro-thiophene-2-carboxylic acid {3- [4- (3-oxo-thiomorpholin-4-yl) -phenyl] -4,5 -Dihydro-isoxazol-5-ylmethyl} -amide.   A compound selected from the group consisting of: 5-chloro-thiophene-2-carboxylic acid [3- (4-cyano-phenyl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-dimethylamino-ethyl) -N-methyl-carbamimidoyl] -phenyl} -4, 5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N-methyl-N-propyl-carbamimidoyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N-ethyl-N-methyl-carbamimidoyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-cyano-phenyl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 1-{[4- (5-{[(5-Chloro-thiophen-2-carbonyl) -amino] -methyl} -isoxazol-3-yl) -phenyl] -imino-methyl} -piperidine-4-carboxylic acid Ethyl ester; 5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-imino-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-azetidin-1-ylidene-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N-ethyl-N-methyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N-methyl-N-propyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-dimethylamino-ethyl) -N-methyl-carbamimidoyl] -phenyl} -isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N-furan-2-ylmethyl-N-methyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-methoxy-ethyl) -N-methyl-carbamimidoyl] -phenyl} -isoxazol-5-ylmethyl) -amide; Methyl 5-chloro-thiophene-2-carboxylate- {3- [4- (N-methylcarbamimidoyl) -phenyl] -isoxazol-5-ylmethyl} -amide; (R) -5-chloro-thiophene-2-carboxylic acid (1- {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide; (R) -5-chloro-thiophene-2-carboxylic acid (1- {3- [4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-yl} -ethyl) -amide; (R) -5-chloro-thiophene-2-carboxylic acid (1- {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide; (S) -5-chloro-thiophene-2-carboxylic acid (1- {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-yl} -ethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -phenyl] -5-methyl-4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {5-methyl-3- [4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -5-methyl-4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -phenyl] -5-methyl-4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 1-{[4- (5-{[(5-chloro-thiophene-2-carbonyl) -amino] -methyl} -5-methyl-4, 5-dihydro-isoxazol-3-yl) -phenyl] -imino-methyl} -piperidine-4-carboxylic acid ethyl ester; 5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-imino-methyl) -phenyl] -5-methyl-4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidin-1-yl-azetidine-1-ylidene-methyl) -phenyl] -5-methyl-4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N-ethyl-N-methyl-carbamimidoyl) -phenyl] -5-methyl-4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid (3- {4- [N- (2-dimethylamino-ethyl) -N-methyl-carbamimidoyl] -phenyl} -5-methyl-4, 5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N-furan-2-ylmethyl-N-methyl-carbamimidoyl) -phenyl] -5-methyl-4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {5-methyl-3- [4- (N-methylcarbamimidoyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (imino-piperidin-1-yl-methyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-morpholin-4-yl-phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid (3- {4- (N, N-dimethyl-carbamimidoyl) -2-[(2-methoxy-ethyl) -methyl-amino] -phenyl} -4, 5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-azepan-1-yl-4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-azepan-1-yl-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-azepan-1-yl-4- (imino-piperidin-1-yl-methyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -isoxazol-5-ylmethyl-amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-dimethylamino-4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-morpholin-4-yl-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -2-morpholin-4-yl-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-morpholin-4-yl-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-morpholin-4-yl-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-methoxy-phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-methoxy-4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-methoxy-phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-methoxy-phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-ethoxy-phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-isopropoxy-phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-isopropoxy-4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-isopropoxy-phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-cyclopentyloxy-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-cyclopentyloxy-4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-cyclopentyloxy-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-cyclohexyloxy-4- (N, N-dimethyl-carbamimidoyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-cyclohexyloxy-4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-cyclohexyloxy-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-methoxy-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-methoxy-4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-methoxy-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-methoxy-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-ethoxy-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (imino-pyrrolidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-ethoxy-4- (imino-piperidin-1-yl-methyl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-isopropoxy-phenyl] -isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-isopropoxy-4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-isopropoxy-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-isopropoxy-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-phenoxy-phenyl] -isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -2-phenoxy-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-phenoxy-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2- (4-methoxy-phenoxy) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2- (4-methoxy-phenoxy) -4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2- (4-methoxy-phenoxy) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-methylsulfanyl-phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -2-methylsulfanyl-phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-methylsulfanyl-phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-piperidin-1-yl-methyl) -2-methylsulfanyl-phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (N, N-dimethyl-carbamimidoyl) -2-methylsulfanyl-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) -2-methylsulfanyl-phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (imino-pyrrolidin-1-yl-methyl) -2-methylsulfanyl-phenyl] -isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-amino-phenyl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-dimethylcarbamoyl-phenyl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (azetidine-1-carbonyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (pyrrolidine-1-carbonyl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid (3- {4-[(2-diethylamino-ethyl) -methyl-carbamoyl] -phenyl} -4, 5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-pyridin-4-yl-phenyl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2'-dimethylaminomethyl-biphenyl-4-yl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2'-piperidin-1-ylmethyl-biphenyl-4-yl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2'-morpholin-4-ylmethyl-biphenyl-4-yl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2 '-{[(2-methoxy-ethyl) -methyl-amino] -methyl} -biphenyl-4-yl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2 '-(4-methyl-piperazin-1-ylmethyl) -biphenyl-4-yl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2 '-{[(2-dimethylamino-ethyl) -methyl-amino] -methyl) -biphenyl-4-yl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (5'-methoxy-2'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (5'-chloro-2'-dimethylaminomethyl-biphenyl-4-yl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (5'-chloro-2'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2'-formyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2'-dimethylaminomethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (5'-methoxy-2'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (2'-dimethylaminomethyl-4'-methoxy-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4'-methoxy-2'-pyrrolidin-1-ylmethyl-biphenyl-4-yl) -isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid [3- (4-pyridin-2-yl-phenyl) -4, 5-dihydro-isoxazol-5-ylmethyl] -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-3-ylamino) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-4-ylamino) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl-amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (methyl-pyridin-4-yl-amino) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid (3- {4-[(3-dimethylamino-propyl) -methyl-amino] -phenyl} -4, 5-dihydro-isoxazol-5-ylmethyl) -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (2-oxo-pyrrolidin-1-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl) -amide; 4- [4- (5-{[(5-chloro-thiophene-2-carbonyl) -amino] -methyl} -4, 5-dihydro-isoxazol-3-yl) -phenyl] -3-oxo-piperazine-1-carboxylic acid benzyl ester; 5-chloro-thiophene-2-carboxylic acid {3- [4- (3-oxo-morpholin-4-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (3-methyl-2-oxo-imidazolidin-1-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (5-oxo- [1, 4] Oxazepan-4-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (pyridin-4-ylamino) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [2-fluoro-4- (4-methyl- [1, 4] diazepan-1-yl) -phenyl] -4, 5-dihydro-isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-3-ylamino) -phenyl] -isoxazol-5-ylmethyl} -amide; 5-chloro-thiophene-2-carboxylic acid {3- [4- (pyridin-4-ylamino) -phenyl] -isoxazol-5-ylmethyl} -amide; And 5-chloro-thiophene-2-carboxylic acid [3- (2'-pyrrolidin-1-ylmethyl-biphenyl-3-yl) -isoxazol-5-ylmethyl] -amide.   A compound selected from the group consisting of: 5-chloro-N-((3- (4- (2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5 Yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (3-fluoro-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxa Sol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (5-fluoro-2-oxopyridin-1 (2H) -yl) phenyl) -4,5 -Dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (3-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxy Sol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (3-methoxy-2-oxopyridin-1 (2H) -yl) phenyl) -4,5 -Dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (3-chloro-2-oxopyridin-1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (4-methyl-2-oxopyridine-1 (2H)- Yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (5-methyl-2-oxopyridine-1) (2H) -Ill) Nyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (5-methoxy-2-oxopyridine-1 (2H ) -Yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (5-chloro-2-oxopyridine) -1 (2H) -yl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4-iodophenyl) isoxazole- 5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (2-oxopyridin-1 (2H) -yl) phenyl) isoxazol-5-yl) methyl) thiol Nen-2-carboxamide; 5-chloro-N-((1- (4- (2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) Methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (3-fluoro-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazole -4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (3-chloro-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1, 2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (3-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazole-4- L) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (3-methoxy-2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3) -Triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (4-methyl-2-oxopyridin-1 (2H) -yl) phenyl) -1H- 1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (5-methyl-2-oxopyridin-1 (2H) -yl) Phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (5-methoxy-2-oxopyridine-1 ( 2H) -yl) phenyl)- H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (5-fluoro-2-oxopyridine-1 (2H)- Yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (5-chloro-2-oxopyridine- 1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (2-oxopiperidine) -1-yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (3-oxomorpholino) phenyl) ) -1H-1,2,3 -Triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (3-oxothiomorpholino) phenyl) -1H-1,2,3-triazol-4- Yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (5-oxo-1,4-oxazepan-4-yl) phenyl) -1H-1,2,3-triazole -4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (2-fluoro-4-iodophenyl) -1H-1,2,3-triazol-4-yl) methyl) Thiophene-2-carboxamide; 5-chloro-N-((1- (2-fluoro-4- (2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazole-4 -Yl) methyl Thiophene-2-carboxamide; 5-chloro-N-((1- (2-fluoro-4- (3-oxomorpholino) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene- 2-carboxamide; 5-chloro-N-((1- (2-hydroxy-4- (2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl ) Methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (2- (4-methylpiperazin-1-yl) -4- (2-oxopyridin-1 (2H) -yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (5- (2-oxopyridin-1 (2H) -yl) pyridine -2-yl)- H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (6- (2-oxopyridin-1 (2H) -yl) pyridine- 3-yl) isoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (2-oxopyridin-1 (2H) -yl) phenyl) -1,2 , 4-oxadiazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) ) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; N-((1- (4- (N, N-dimethylcarbamimidoyl) phenyl) -1H-1 , 2,3-Tria Sol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; N-((1- (4- (N-ethyl-N-methylcarbamimidoyl) phenyl) -1H-1,2,3 -Triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; N-((1- (4- (N-methyl-N-propylcarbamimidoyl) phenyl) -1H-1,2, 3-triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; N-((1- (4- (N- (2-methoxyethyl) -N-methylcarbamimidoyl) phenyl)- 1H-1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; N-((1- (4- (azetidin-1-yl (imino) methyl) phenyl) -1H -1,2 3-triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((1- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1H-1 , 2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (imino (piperidin-1-yl) methyl) phenyl) -1H-1, 2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; N-((1- (4- (N, N-dimethylcarbamimidoyl) -2-fluorophenyl) -1H-1,2 , 3-Triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; N-((1- (4- (azetidin-1-yl (imino) methyl) -2-fluorophenyl) -1H 1,2,3-triazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((1- (2-fluoro-4- (imino (pyrrolidin-1-yl) Methyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (2-fluoro-4- (imino (piperidine-1) -Yl) methyl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (2-fluoro-4- (1- Methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; N-((1- (4- (N, N-zime Tylcarbamimidoyl) phenyl) -1H-pyrazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((1- (4- (1-methyl-4,5- Dihydro-1H-imidazol-2-yl) phenyl) -1H-pyrazol-4-yl) methyl) thiophene-2-carboxamide; N-((1- (4- (azetidin-1-yl (imino) methyl) phenyl) ) -1H-pyrazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((1- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1H -Pyrazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (4- (imino (piperidin-1-yl) methyl) phenyl) -1H- Lazol-4-yl) methyl) thiophene-2-carboxamide; N-((5- (4- (N, N-dimethylcarbamimidoyl) phenyl) isoxazol-3-yl) methyl) -5-chlorothiophene- 2-Carboxamide; 5-chloro-N-((5- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) isoxazol-3-yl) methyl) thiophene-2- Carboxamide; 5-chloro-N-((5- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) isoxazol-3-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-(( 5- (4- (imino (piperidin-1-yl) methyl) phenyl) isoxazol-3-yl) methyl) thiophene-2-carboxamide; N-((3- 4- (N, N-dimethylcarbamimidoyl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((3- (4- (1-Methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N -((3- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-(( 3- (4- (imino (piperidin-1-yl) methyl) phenyl) -1,2,4-oxadiazol-5-yl) methyl) thiophene-2-carboxamide; N-((2- (4- (N , N-dimethylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((2- (4- (1-methyl-4,5 -Dihydro-1H-imidazol-2-yl) phenyl) oxazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((2- (4- (imino (pyrrolidin-1-yl) methyl) ) Phenyl) oxazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((2- (4- (imino (piperidin-1-yl) methyl) phenyl) oxazol-4-yl) methyl ) Thiophene-2-carboxamide; 1-((4- (4-((2-chlorothiophene-5-carboxamido) methyl) oxazol-2-yl) phenyl (Imino) methyl) piperidine-4-carboxylate; N-((2- (4- (N-ethyl-N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene N-((2- (4- (N-methyl-N-propylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; N- ( (2- (4- (N- (2- (dimethylamino) ethyl) -N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; N- ( (2- (4- (N- (2-methoxyethyl) -N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophen-2- 1-((4- (4-((2-chlorothiophene-5-carboxamido) methyl) oxazol-2-yl) phenyl) (imino) methyl) piperidine-4-carboxamide; N-((2- ( 4- (N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; N-((2- (4- (N- (furan-2-ylmethyl) -N-methylcarbamimidoyl) phenyl) oxazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; N-((2- (4- (N, N-dimethylcarbamimidoyl) phenyl) ) Thiazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((2- (4- (1-methyl-4,5-dihydro -1H-imidazol-2-yl) phenyl) thiazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((2- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) ) Thiazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((2- (4- (imino (piperidin-1-yl) methyl) phenyl) thiazol-4-yl) methyl) thiophene 2-carboxamide; 1-((4- (4-((2-chlorothiophen-5-carboxamido) methyl) thiazol-2-yl) phenyl) (imino) methyl) piperidine-4-carboxylate; N- ((2- (4- (N- (2- (dimethylamino) ethyl) -N-methylcarbamimidoyl) phenyl) thiazol-4-yl) methyl) -5 Lorothiophene-2-carboxamide; N-((2- (4- (N- (furan-2-ylmethyl) -N-methylcarbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene 2-carboxamide; N-((2- (4- (N-methyl-N- (prop-2-ynyl) carbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene-2 -Carboxamide; N-((2- (4- (N-methylcarbamimidoyl) phenyl) thiazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((4 -(4- (imino (pyrrolidin-1-yl) methyl) phenyl) oxazol-2-yl) methyl) thiophene-2-carboxamide; N-((4- (4- (N, N-di Tylcarbamimidoyl) phenyl) thiazol-2-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((4- (4- (1-methyl-4,5-dihydro-1H -Imidazol-2-yl) phenyl) thiazol-2-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((4- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) thiazol) 2-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((4- (4- (imino (piperidin-1-yl) methyl) phenyl) thiazol-2-yl) methyl) thiophene-2 Carboxamide; N-((1- (4- (N, N-dimethylcarbamimidoyl) phenyl) -1H-imidazol-4-yl) methyl) -5-chlorothio Fen-2-carboxamide; 5-chloro-N-((1- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -1H-imidazol-4-yl) methyl ) Thiophene-2-carboxamide; N-((1- (4- (azetidin-1-yl (imino) methyl) phenyl) -1H-imidazol-4-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((1- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -1H-imidazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N- ( (1- (4- (imino (piperidin-1-yl) methyl) phenyl) -1H-imidazol-4-yl) methyl) thiophene-2-carboxamide; N-((5- (4- N, N-dimethylcarbamimidoyl) phenyl) pyridin-3-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((5- (4- (1-methyl-4, 5-dihydro-1H-imidazol-2-yl) phenyl) pyridin-3-yl) methyl) thiophene-2-carboxamide; N-((5- (4- (azetidin-1-yl (imino) methyl) phenyl) Pyridin-3-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((5- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) pyridin-3-yl) Methyl) thiophene-2-carboxamide; 5-chloro-N-((5- (4- (imino (piperidin-1-yl) methyl) phenyl) pyridin-3-yl) methyl Thiophene-2-carboxamide; N-((5- (4- (N, N-dimethylcarbamimidoyl) phenyl) -2-fluorophenyl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro- N-((5- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) -2-fluorophenyl) methyl) thiophene-2-carboxamide; 5-chloro-N- ((5- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) -2-fluorophenyl) methyl) thiophene-2-carboxamide; N-((3- (4- (N, N-dimethylcarba Mumidyl) phenyl) -4-fluorophenyl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((3- (4- (1-methyl -4,5-dihydro-1H-imidazol-2-yl) phenyl) -4-fluorophenyl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (imino (pyrrolidine-1 -Yl) methyl) phenyl) -4-fluorophenyl) methyl) thiophene-2-carboxamide; N-((3- (4- (N, N-dimethylcarbamimidoyl) phenyl) phenyl) methyl) -5 Chlorothiophene-2-carboxamide; 5-chloro-N-((3- (4- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) phenyl) phenyl) methyl) thiophene-2-carboxamide 5-chloro-N-((3- (4- (imino (pyrrolidin-1-yl) methyl) phenyl) phenyl) methyl) thiophene-2-carboxyl; 5-Chloro-N-((1- (6- (4-methyl-1,4-diazepan-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl ) Methyl) thiophene-2-carboxamide; N-((1- (6- (1,4-diazepan-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) Methyl) -5-chlorothiophene-2-carboxamide; N-((1- (6- (1,4-oxazepan-4-yl) pyridin-3-yl) -1H-1,2,3-triazol-4 -Yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((1- (6-morpholinopyridin-3-yl) -1H-1,2,3-triazol-4-yl) Methyl) thiophene-2-carboxamide; 5-chloro N-((1- (6- (3-oxomorpholino) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N- ((1- (6- (2-oxopiperidin-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro- N-((1- (6- (2-oxopyridin-1 (2H) -yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide 5-chloro-N-((1- (6- (piperazin-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (6 -(4-Methylpiperazin-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((1- (6- (piperidin-1-yl) pyridin-3-yl) -1H-1,2,3-triazol-4-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- ( 4- (8- (trifluoromethyl) quinolin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (7- (trifluoromethyl) quinolin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-(( -(4- (6- (trifluoromethyl) quinolin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-(( 3- (4- (Quinolin-6-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- ( 2,5-dihydro-1H-pyrrole-1-carbonyl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4 -(2,5-dihydro-1H-pyrrole-1-carbonyl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; N-((3- 4-((2-hydroxypropyl) carbamoyl) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) -5-chlorothiophene-2-carboxamide; 5-chloro-N-((3- ( 4- (3-methylpyridin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- ( 2-Ethoxypyridin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3- (4- (3,5 -Dichloropyridin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide; and 5-chloro-N-((3 -(4- (3- (trifluoromethyl) pyridin-4-ylamino) phenyl) -4,5-dihydroisoxazol-5-yl) methyl) thiophene-2-carboxamide. Pharmaceutical compositions comprising a compound of pharmaceutically acceptable excipients and the claims 1-28, wherein. Therapeutically effective amount containing, pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis of claims 1 to 28 A compound according. Acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, obstructive coronary thrombosis after thrombolytic treatment or coronary angioplasty, thrombotic cerebrovascular syndrome, embolic stroke, thrombotic Stroke, transient ischemic stroke, venous thrombosis, deep vein thrombosis, pulmonary embolism, coagulopathy, disseminated intravascular coagulation, thrombocytopenic thrombotic purpura, obstructive thrombotic vasculitis, heparin-induced thrombocytopenia Thrombotic diseases associated with infectious diseases, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with the use of devices such as the heart or other intravascular catheterization, intra-aortic balloon pumps, coronary stents or heart valves, and 32. The pharmaceutical composition of claim 30 , wherein the pharmaceutical composition is selected from the group consisting of conditions requiring prosthetic tube fitting. A method for inhibiting the coagulation of a blood sample, the method comprising the step of contacting a compound of claim 1 to 28 wherein the sample.